In one aspect, this invention discloses benzoxazinone and benzothiazinone compounds which display inhibitory effects on serine proteases such as factor Xa, thrombin, and/or factor VIIa. The invention also discloses pharmaceutically acceptable salts of the compounds, pharmaceutically acceptable compositions comprising the compounds or their salts, and methods of using them as therapeutic agents for treating or preventing disease states in mammals characterized by abnormal thrombosis.
In economically developed countries, cardiovascular disease still represents a major cause of mortality. In particular, abnormal coagulation and inappropriate thrombus formation within blood vessels precipitates many acute cardiovascular disease states. While it has long been recognized that a variety of plasma proteins such as fibrinogen, serine proteases. and cellular receptors are involved in hemostasis, it is the abnormal regulation that has emerged as important contributing factors to cardiovascular disease. Thrombin can be considered the key or principal regulatory enzyme in the coagulation cascade; it serves a pluralistic role as both a positive and negative feedback regulator in normal hemostasis. However, in some pathologic conditions, the former is amplified through catalytic activation of cofactors required for thrombin generation such as factor Xa. Factor Xa, as part of the prothrombinase complex composed of nonenzymatic cofactor Va, calcium ions, and a phospholipid membrane surface regulates the generation of thrombin from its zymogen prothrombin. Furthermore, the location of the prothrombinase complex at the convergence of both the intrinsic and extrinsic coagulation pathways suggests that inhibition of factor Xa, and hence thrombin generation, may be a viable approach to limiting the procoagulant activity of thrombin.
Indeed, ample evidence exists for the role of factor Xa inhibitors as anticoagulants. Antistasin, a potent inhibitor of blood coagulation factor Xa from the Mexican leech: Haementeria officinalis, displays antithrombotic activity in various models of arterial and venous thrombosis (Lapatto et al., Embo. J., 1997:5151-5161). Other protein or polypeptide factor Xa inhibitors include recombinant tick anticoagulant peptide (rTAP), which is known to accelerate the recombinant tissue plasminogen activator mediated clot lysis and prevent acute reocclusion in the dog, hence indicating factor Xa inhibitors may be useful as an adjunct to thrombolytic therapy (Mellott et al., Fibrinolysis, 1993:195-202). Furthermore, in a canine coronary artery electrolytic lesion model, rTAP was demonstrated to reduce thrombus mass and time to occlusion in the absence of dramatic hemodynamic or hemostatic changes indicating the primary role for factor Xa in the process of arterial thrombosis (Lynch et al., Thromb. Haemostasis, 1995:640-645; Schaffer et al., Circulation, 1991:1741-1748). On the venous side, rTAP was also demonstrated to reduce fibrin deposition in a rabbit model of venous thrombosis while having little affect on systemic hemostatic parameters (Fioravanti et al., Thromb. Res., 1993:317-324). In addition to these relatively high molecular weight proteins that are not suitable as oral antithrombotic agents, there also exist examples of low molecular weight factor Xa inhibitors. In particular Dx9065a, a low molecular weight synthetic factor Xa inhibitor, has also shown antithrombotic potential in various experimental thrombosis rat models. In both arteriovenous shunt and venous stasis models, inhibition of thrombus formation was achieved at doses that had little effect on APTT, indicating that DX9065a is effective in preventing thrombosis and hence has therapeutic antithrombotic potential (Wong et al., Thromb. Res., 1996:117-126).
The majority of factor Xa inhibitors known to date have been previously summarized in two reviews (Edmunds et al., Annual Reports in Medicinal Chemistry, 1996:51 and Kunitada and Nagahara, Curr. Pharm. Des., 1996:531-542). However, it is readily apparent that there still exists a need for more effective agents that regulate factor Xa proteolytic activity.
Some benzoxazinones and benzothiazinones have been reported and these compounds have displayed marked pharmacological activity:
Moriyama et al., Biol. Pharm. Bull, 1997:701-703;
Gezginci et al., Farmaco, 1997:255-256;
Sastry et al., Indian J. Chem., Sect. B, 1989:882-884;
U.S. Pat. No. 6,807,18;
Bomschein et al., Pharmazie, 1977:695-697 and Pfeifer et al., Pharmazie, 1977:587-592;
Japanese Application 60166674;
European Application 116368;
Japanese Application 01272524;
U.S. Pat. No. 4,786,635;
Fujita M. et al., J. Med Chem., 1990:1898;
Japanese Application 03118380;
Japanese Application 09227561;
Shridhar et al., Indian J. Chem., Sect. B, 1985;24B(12):1263-1267;
Bornschein et al., Pharmazie, 1977;32(11):695-697 and 1977;32(10):587-592;
Thuillier et al., Eur. J Med Chem.xe2x80x94Chim. Ther., 1975;10(1):37-42;
German Patent 2044530; and
U.S. Pat. No. 3,401,166.
None of the above articles set forth above, however, disclose or suggest compounds set forth herein that are inhibitors of serine proteases involved in the blood coagulation cascade.
One object of the present invention is to provide serine protease inhibitors that display inhibitory activity towards enzymes involved in the coagulation cascade and principally the target enzymes, factor Xa, thrombin, and factor VIIa.
A further object of the present invention is to provide serine protease inhibitors that display inhibitory activity towards the target enzyme factor Xa and are provided for in a pharmacologically acceptable state.
Still a further object of the present invention is to provide for the use of these factor Xa inhibitors and formulations thereof as anticoagulant and factor Xa inhibitory agents.
Yet a further object of the present invention is to provide for the use of these factor Xa inhibitors and formulations thereof for therapeutic treatment of various thrombotic maladies.
A further object of the present invention is a process for the synthesis of these low molecular weight thrombin inhibitors. The enzyme inhibitors of the present invention are encompassed by the structure of general Formula 1 set forth below.
The present invention meets these objectives and provides for novel compounds that display antithrombotic activity. More specifically, the present invention provides for novel compounds that display antithrombotic activity via the inhibition of factor Xa as reflected in Formula 1, or pharmaceutically acceptable salts or prodrug forms thereof. The present invention also provides pharmaceutically acceptable compositions comprising the novel compounds or their salts or prodrug forms, and methods of using them as therapeutic agents for treating or preventing disease states in mammals characterized by abnormal thrombosis.
Thus in a first embodiment. the present invention provides novel compounds of Formula 1: 
or stereolsomers or pharmaceutically acceptable salt forms or prodrugs thereof, wherein:
A is selected from O, S, S(xe2x95x90O), S(xe2x95x90O)(xe2x95x90O), OCH2, CH2O, SCH2, S(xe2x95x90O)CH2, S(xe2x95x90O)(xe2x95x90O)CH2, CH2S, CH2S(xe2x95x90O), CH2S(xe2x95x90O)(xe2x95x90O);
B is selected from hydrogen, cycloalkyl, heteroalkyl, cycloalkylalkyl, heteroalkylalkyl, aryl, arylalkyl, heterocycle, heterocycloalkyl, each optionally substituted with R1 and R2;
D is selected from H, (C3-20)alkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heteroalkylalkyl, aryl, arylalkyl, heterocycle, heterocycloalkyl, each optionally substituted with R1 and R2;
E is absent or selected from O, S, NH;
F is selected from N, NCH2, CH2N;
G is absent or selected from alkyl, alkyl interrupted by one or more heteroatoms, cycloalkyl, cycloalkyl interrupted by one or more heteroatoms;
J is absent or selected from aryl or heterocycle each optionally substituted with R1 and R2;
K is absent or selected from an alkyl, alkyl interrupted by one or more heteroatoms, cycloalkyl interrupted by one or more heteroatoms, cycloalkylalkyl interrupted by one or more heteroatoms, each optionally substituted with R1 and R2;
L is selected from H, chlorine, fluorine, bromine, iodine, OH, O(alkyl), amine, alkyl, fluoroalkyl, amide, NO2, SH, S(O)n(alkyl), SO3H, SO3alkyl, nitrile aldehyde, ketone, acid, ester, urea, Oalkylamide, Oalkylester, Oalkylacid, Nalkylacid, alkylamine, alkylamide, alkylketone, alkylacid, alkylester, alkylurea, Nalkylamide, Nalkylester, NC(xe2x95x90O)alkyl, NC(xe2x95x90O)aryl, NC(xe2x95x90O)cycloalkyl, NC(xe2x95x90O)cycloalkylalkyl, NC(xe2x95x90O) alkylaryl, R1. R2;
R1 is selected from H, amine, alkylamine, amide, C(xe2x95x90NH)NHNH2, alkylC(xe2x95x90NH)NHNH2, C(xe2x95x90NH)NHOH, alkylC(xe2x95x90NH)NHOH, NHC(xe2x95x90NH)NH2, alkylNHC(xe2x95x90NH)NH2, C(xe2x95x90S)NH2, alkylC(xe2x95x90S)NH2, C(xe2x95x90NH)alkyl, alkylC(xe2x95x90NH)alkyl, C(xe2x95x90NR3)N(R4)(R5), alkylC(xe2x95x90NR3)N(R4)(R5);
R2 is selected from H, chlorine, fluorine, bromine, iodine, OH, Oalkyl, amine, alkylaldehyde, alkylamide, alkylester, alkylketone, alkylacid, Oalkylamide. Oalkylacid, Oalkylester, aninealkylacid, aminealkylamide, aminealkylester, NC(xe2x95x90O)alkyl, NC(xe2x95x90O)aryl, NC(xe2x95x90O)cycloalkyl, NC(xe2x95x90O)alkylaryl, alkylamine, amide, aldehyde, ester, ketone, NO2, SH, S(O)n(C1-10alkyl), SO3H, SO3alkyl, CHO, acid, alkyl, C(xe2x95x90NH)alkyl, C(xe2x95x90NH)NHNH2, alkylC(xe2x95x90NH)NHNH2, C(xe2x95x90NH)NHOH, alkylC(xe2x95x90NH)NHOH, NHC(xe2x95x90NH)NH2, alkylNHC(xe2x95x90NH)NH2, C(xe2x95x90S)NH2, alkylC(xe2x95x90S)NH2, alkylC(xe2x95x90NH)alkyl, C(xe2x95x90NR3)N(R4)(R5), alkylC(xe2x95x90NR3)N(R4)(R5);
R3, R4, and R5 are a hydrogen atom, alkyl group having 1 to 4 carbon atoms optionally interrupted by a heteroatom, or R4 and R5 are bonded to form xe2x80x94(CH2)pxe2x80x94Wxe2x80x94(CH2)qxe2x80x94, wherein p and q are an integer of 2 or 3, a certain position on the methylene chain is unsubstituted or substituted by an alkyl group having 1 to 4 carbon atoms, W is a direct bond, xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94N(R6)xe2x80x94, or xe2x80x94S(O)rxe2x80x94 wherein R6 is H or alkyl, and r is 0 or 1 or 2;
n is selected from 0, 1, 2;
X1 is C or N;
X2 is C or N;
X3 is C or N; and
X4 is C or N.
Preferred compounds according to this invention have the Formula 2: 
or stereoisomers or pharmaceutically acceptable salts, esters, amides, or prodrugs thereof, wherein A, B, E, G, J, K, and L are defined as above.
Another preferred group of compounds have the Formula 3: 
or stereoisomers or pharmaceutically acceptable salts, esters, amides, or prodrugs thereof, wherein B, G, J, K, and L are defined as above.
Another preferred group of compounds have the Formula 4: 
or stereoisomers or pharmaceutically acceptable salts, esters, amides, or prodrugs thereof, wherein B, G, J, K, and L are defined as above.
Even more preferred compounds have the Formula 5: 
or stereoisomers or pharmaceutically acceptable salts, esters, amides, or prodrugs thereof, wherein R1, R2, G, J, K, and L are as defined above.
Another more preferred group of compounds have the Formula 6: 
or stereoisomers or pharmaceutically acceptable salts, esters, amides, or prodrugs thereof, wherein R1, R2, G, J, K, and L are as defined above.
The most preferred compounds provided by this invention are compounds of Formulas 7 and 8: 
or stereoisomers or pharmaceutically acceptable salts, esters, amides, or prodrugs thereof, wherein
R7 is (3-amidino)phenyl, (3-hydroxy)phenyl, [3-hydroxylamino(imino)methyl]-phenyl, [3-hydrazino(imino)methyl]-phenyl, (3-aminomethyl)phenyl, (3-amino)phenyl, (3-methylamino)phenyl, (3-dimethylamino)phenyl, (5-amidino-2-hydroxy)phenyl, (1-amidino)piperid-3-yl, (5-amidino-2-methoxy)phenyl, (1-amidino)pyrrolid-3-yl, (5-amidino)thien-2-yl, (5-amidino)furan-2-yl, (5-amidino)-1,3-oxazol-2-yl, (2-amidino)-1,3-oxazol-5-yl, 1H-pyrazol-5-yl, tetrahydro- 1H-pyrazol-3-yl, (1-amidino)tetrahydro-1H-pyrazol-3-yl, (2-amidino)-1H-imidazol-4-yl, (2-amino)-1H-imidazol-4-yl, (5-amidino)-1H-imidazol-2-yl, (5-amino)-1H-imidazol-2-yl, pyridin-3-yl, (4-amino)pyridin-3-yl, (4-dimethylamino)pyridin-3-yl, (6-amino)pyridin-2-yl, (6-amidino)pyridin-2-yl, (2-amino)pyridin-4-yl, (2-amidino)pyridin-4-yl, (2-amidino)pyrimid-4-yl, (2-amino)pyrimidin4-yl, (4-amidino)pyrimid-2-yl, (4-amino)pyrimidin-2-yl, (6-amidino)pyrazin-2-yl, (6-amino)pyrazin-2-yl, (4-amidino)-1,3,5-triazin-2-yl, (4-amino)-1,3,5-triazin-2-yl, (3-amidino)-1,2,4-triazin-5-yl, (3-amino)-1,2,4-triazin-5-yl, (3-amidino)benzyl, (3-amino)benzyl, (3-aminomethyl)benzyl, (1-amidino)piperid-3-ylmethyl, (1-amidino)pyrrolid-3-ylmethyl, (5-amidino)thien-2-ylmethyl, (5-amidino)furan-2-ylmethyl, (5-amidino)oxazol-2-ylmethyl, (2-amidino)imidazol-5-ylmethyl, (5-amidino)imidazol-2-ylmethyl, (6-amidino)pyridin-2-ylmethyl, (6-amino)pyridin-2-ylmethyl, (2-amidino)pyrimidin-4-ylmethyl, (2-amino)pyrimidin-4-ylmethyl, (4-amidino)pyrimidin-2-ylmethyl, (4-amino)pyrimidin-2-ylmethyl, (6-amidino)pyrazin-2-ylmethyl, (6-amino)pyrazin-2-ylmethyl, 3-aminocyclohexyl, 3-amidinocyclohexyl, 3-aminocyclohexylmethyl, 3-amidinocyclohexylmethyl, 3-aminocyclopentyl, 3-amidinocyclopentyl, 3-aminocyclopentylmethyl, and 3-amidinocyclopentylmethyl;
R8 is Br, I, C2H5, H, Cl, F, SH, SMe, CF3, CH3, CO2H, CO2Me, CN, C(xe2x95x90NH)NH2, C(xe2x95x90NH)NHOH, C(xe2x95x90NH)NHNH2, C(xe2x95x90O)NH2, CH2OH, CH2NH2, NO2, OH, OMe, OCH2Ph, OCH2CO2H, O(CH2)2CO2H, O(CH2)3CO2H, NHCH2CO2H, NH(CH2)2CO2H, NH(CH2)3CO2H, OCH2CH2OH, OCH2(1H-tetrazol-5-yl), NH2, NHButyl, NMe2, NHPh, NHCH2Ph, NHC(xe2x95x90O)Me, NHC(xe2x95x90O)c-Hexyl, NHC(xe2x95x90O)CH2c-Hexyl, NHC(xe2x95x90O)Ph. NHC(xe2x95x90O)CH2Ph, NHS(xe2x95x90O)2Me, NHS(xe2x95x90O)2c-Hexyl, NHS(xe2x95x90O)2CH2C-Hexyl, NHS(xe2x95x90O)2Ph, and NHS(xe2x95x90O)2CH2Ph;
R9 is (CH2)5, (CH2)4, (CH2)6, CH2C(xe2x95x90O)NHCH2CH2, CH2CH2NHC(xe2x95x90O)CH2, (CH2)2NH(CH2)2, (CH2)2O(CH2)2, C6H4, CH2C6H4, C6H4CH2, C6H10, CH2C6H10, C6H10CH2, C5H8, CH2C5H8, C5H8CH2, and CH2CHxe2x95x90CHCH2CH2; and
R10 is piperidinyl, 2,6-dimethylpiperidinyl, 2,2,6,6-tetrainethyl-piperidinyl-4-one, 2,2,6,6-tetramethyl piperidinyl, (2-carboxy)piperidinyl, (3-carboxy)piperidinyl, (4-carboxy)piperidinyl, 3,5-dimethylpiperidinyl, (4-hydroxy)piperidinyl, (2-imino)piperidinyl, piperidin-4-one-yl, (2-dimethylaminomethyl)-piperidinyl, (4-dimethylamino)-piperidinyl, (4-sulphonyloxy)-piperidinyl, (2-phenyl)piperidinyl, 2,5-dimethylpyrrolidinyl, pyrrolidinyl, (2-carboxy)pyrrolidinyl, (3-N-acetyl-N-methyl)pyrrolidinyl, (3-amino)pyrrolidinyl, (2,5-bis-methoxymethyl)-pyrrolidinyl, 2-hydroxymethyl-pyrrolidinyl, 2-hydroxymethyl-5-methyl-pyrrolidinyl, diisopropylamino, diethylamino, methylamino, 1-methyl-4,5-dihydro-1H-imidazol-2-yl, 2,5-dimethyl-1H-1-imidazolyl, morpholinyl, 2,6-dimethylmorpholinyl, piperazinyl, 2,6-dimethylpiperazinyl, 1H-pyrazolyl, tetrahydro-1H-pyrazolyl, and 2,5-dimethyltetrahydro-1H-1-pyrazolyl.
In one embodiment of Formulas 7 and 8, R8, R9, and R10 are as above and R7 is (2-hydroxy, 5-amidino)phenyl. In another embodiment of Formulas 7 and 8, R7, R9, and R10 are as above and R8 is H. In another embodiment of Formulas 7 and 8, R7, R8, and R10 are as above and R9 is (CH2)5. In another embodiment of Formulas 7 and 8, R7, R8, and R10 is 2,6-dimethylpiperidinyl. In another embodiment of Formulas 7 and 8, R7 is as defined above and R8 is H, R9 is (CH2)5 and R10 is 2,6-dimethylpiperidinyl. In another embodiment of Formulas 7 and 8, R7 is as defined above and R8 is H, R9 is (CH2)5 and R10 is 2,5-dimethylpyrrolidinyl.
Representative compounds of the present invention include:
3-(4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)-4-methoxybenzenecarboximidamide;
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)benzenecarboximidamide:
4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-(3-hydroxyphenyl)-2H-1,4-benzothiazin-3(4H)-one;
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)-N-hydroxybenzenecarboximidamide;
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)-N-hydroxybenzenecarboximidamide;
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)benzenecarboximidohydrazide;
2-[3-(Aminomethyl)phenyl]-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2H-1,4-benzothiazin-3(4H)-one;
2-(3-Aminophenyl)-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2H-1,4-benzothiazin-3(41)-one;
4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-[3-(methylamino)phenyl]-2H-1,4-benzothiazin-3(4H)-one;
2-[3-(Dimethylamino)phenyl]-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2H-1,4-benzothiazin-3(4H)-one;
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)-4-hydroxybenzenecarboximidamide;
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)tetrahydro-1(2H)-pyridinecarboximidamide;
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)-1-pyrrolidinecarboximidamide;
5-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)-2-thiophenecarboximidamide;
5-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)-2-furancarboximidamide;
2-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)-1,3-oxazole-5-carboximidamide;
5-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)-1,3-oxazole-2-carboximidamide;
4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-(1H-pyrazol-5-yl)-2H-1,4-benzothiazin-3(4H)-one;
5-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)-1-pyrazolidinecarboximidamide;
4-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)-1H-imidazole-2-carboximidamide;
2-(2-Amino-1H-imidazol-4-yl)-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2H-1,4-benzothiazin-3(4H)-one;
2-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)-1H-imidazole-5-carboximidamide;
2-(5-Amino-1H-imidazol-2-yl)-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2H-1,4-benzothiazin-3(4H)-one;
4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-(3-pyridinyl)-2H-1,4-benzothiazin-3(4H)-one;
2-(4-Amino-3-pyridinyl)-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2H-1,4-benzothiazin-3(4H)-one;
2-[4-(Dimethylamino)-3-pyridinyl]-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2H-1,4-benzothiazin-3(4H)-one;
2-(6-Amino-2-pyridinyl)-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2H-1,4-benzothiazin-3(4H)-one;
6-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)-2-pyridinecarboximidamide;
2-(2-Amino4-pyridinyl)-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2H-1,4-benzothiazin-3(4H)-one;
4-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)-2-pyridinecarboximidamide;
4-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)-2-pyrimidinecarboximidamide;
2-(2-Amino-4-pyrimidinyl)4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2H-1,4-benzothiazin-3(4H)-one;
2-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)-4-pyrimidinecarboximidamide;
2-(4-Amino-2-pyrimidinyl)-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2H-1,4-benzothiazin-3(4H)-one;
6-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)-2-pyrazinecarboximidamide;
2-(6-Amino-2-pyrazinyl)-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2H-1,4-benzothiazin-3(4H)-one;
4-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)-1,3,5-triazine-2-carboximidamide;
2-(4-Amino-1,3,5-triazin-2-yl)-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2H-1,4-benzothiazin-3(4H)-one;
5-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)-1,2,4-triazine-3-carboximidamide;
2-(3-Amino-1,2,4-triazin-5-yl)-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2H-1,4-benzothiazin-3(4H)-one;
3-[(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)methyl]benzenecarboximidamide;
2-(3-Aminobenzyl)-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2H-1,4-benzothiazin-3(4H)-one;
2-[3-(Aminomethyl)benzyl]-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2H-1,4-benzothiazin-3(41)-one;
3-[(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)methyl]tetrahydro-1(2H)-pyridinecarboximidamide;
3-[(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)methyl]-1-pyrrolidinecarboximidamide;
5-[(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)methyl]-2-thiophenecarboximidamide;
5-[(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)methyl]-2-furancarboximidamide;
2-[(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)methyl]-1,3-oxazole-5-carboximidamide;
5-[(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)methyl]-1H-imidazole-2-carboximidamide;
2-[(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)methyl]-1H-imidazole-5-carboximidamide;
6-[(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)methyl]-2-pyridinecarboximidamide;
2-[(6-Amino-2-pyridinyl)methyl]-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2H-1,4-benzothiazin-3(4H)-one;
4-[(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)methyl]-2-pyrimidinecarboximidamide;
2-[(2-Amino-4-pyrimidinyl)methyl]4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2H-1,4-benzothiazin-3(4H)-one;
2-[(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)methyl]-4-pyrimidinecarboximidamide;
2-[(4-Amino-2-pyrimidinyl)methyl]-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2H-1,4-benzothiazin-3(4H)-one;
6-[(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)methyl]-2-pyrazinecarboximidamide;
2-[(6-Amino-2-pyrazinyl)methyl]4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2H-1,4-benzothiazin-3(4H)-one;
2-(3-Aminocyclohexyl)-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2H-1,4-benzothiazin-3(4H)-one;
3-(4-5-[(2R,69)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)cyclohexanecarboximidamide;
2-[(3-Aminocyclohexyl)methyl]-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2H-1,4-benzothiazin-3(4H)-one;
3-[(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)methyl]cyclohexanecarboximidamide;
2-(3-Aminocyclopentyl)-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2H-1,4-benzothiazin-3(4H)-one;
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)cyclopentanecarboximidamide;
2-[(3-Aminocyclopentyl)methyl]-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2H-1,4-benzothiazin-3(4H)-one;
3-[(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)methyl]cyclopentanecarboximidamide;
3-(4-4-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]butyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)benzenecarboximidamide;
3-(4-6-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]hexyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)benzenecarboximidamide;
2-(2-3-[Amino(imino)methyl]phenyl-3-oxo-2,3-dihydro-4H-1,4-benzothiazin-4-yl)-N-2-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]ethylacetamide;
3-(2-3-[Amino(imino)methyl]phenyl-3-oxo-2,3-dihydro-4H-1,4-benzothiazin-4-yl)-N-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]methylpropanamide;
3-4-[2-(2-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]ethylamino)ethyl]-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-ylbenzenecarboximidamide;
3-[4-(2-2-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]ethoxyethyl)-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl]benzenecarboximidamide;
3-(4-4-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]phenyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)benzenecarboximidamide;
3-(4-4-[(2R,6S)-2,6-Dimethyl tetrahydro-1(2H)-pyridinyl]benzyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)benzenecarboximidamide;
3-[4-(4-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]methylphenyl)-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl]benzenecarboximidamide.
3-(4-4-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]cyclohexyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)benzenecarboximidamide;
3-[4-(4-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]cyclohexylmethyl)-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl]benzenecarboximidamide;
3-[4-(4-[(2R,6S)-2,6-Dimethyltetrahydro-1(2 H)-pyridinyl]methylcyclohexyl)-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl]benzenecarboximidamide;
3-(4-3-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]cyclopentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)benzenecarboximidamide;
3-[4-(3-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]cyclopentylmethyl)-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl]benzenecarboximidamide;
3-[4-(3-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]methylcyclopentyl)-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl]benzenecarboximidamide;
3-(4-(E)-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]-2-pentenyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)benzenecarboximidamide;
3-[3-Oxo-4-(5-piperidinopentyl)-3,4-dihydro-2H-1,4-benzothiazin-2-yl]benzenecarboximidamide;
3-3-Oxo-4-[5-(2,2,6,6-tetramethylpiperidino)pentyl]-3,4-dihydro-2H-1,4-benzothiazin-2-ylbenzenecarboximidamide;
1-[5-(2-3-[Amino(imino)methyl]phenyl-3-oxo-2,3-dihydro-4H-1,4-benzothiazin-4-yl)pentyl]-2-piperidinecatboxylic acid;
1-[5-(2-3-[Amino(imino)methyl]phenyl-3-oxo-2,3-dihydro-4H-1,4-benzothiazin-4-yl)pentyl]-3-piperidinecarboxylic acid;
1-[5-(2-3-[Amino(imino)methyl]phenyl-3-oxo-2,3-dihydro-4H-1,4-benzothiazin-4-yl)pentyl]-4-piperidinecarboxylic acid;
3-4-[5-(3,5-Dimethylpiperidino)pentyl]-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-ylbenzenecarboximidamide;
3-4-[5-(4-Hydroxypiperidino)pentyl]-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-ylbenzenecarboximidamide;
3-4-[5-(2-Iminopiperidino)pentyl]-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-ylbenzenecarboximidamide;
3-3-Oxo-4-[5-(4-oxopiperidino)pentyl]-3,4-dihydro-2H-1,4-benzothiazin-2-ylbenzenecarboximidamide;
3-[4-(5-2-[(Dimethylamino)methyl]piperidinopentyl)-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl]benzenecarboximidainide;
3-(4-5-[4-(Dimethylamino)piperidino]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)benzenecarboximidamide;
1-[5-(2-3-[Amino(imino)methyl]phenyl-3-oxo-2,3-dihydro-4H-1,4-benzothiazin-4-yl)pentyl]-4-piperidinesulfonic acid;
3-3-Oxo-4-[5-(2-phenylpiperidino)pentyl]-3,4-dihydro-2H-1,4-benzothiazin-2-ylbenzenecarboximidamide;
3-4-[5-(2,5-Dimethyl-1-pyrrolidinyl)pentyl]-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-ylbenzenecarboximidamide;
3-3-Oxo-4-[5-(1-pyrrolidinyl)pentyl]-3,4-dihydro-2H-1,4-benzothiazin-2-ylbenzenecarboximidamide;
1-[5-(2-3-[Amino(imino)methyl]phenyl-3-oxo-2,3-dihydro-4H-1,4-benzothiazin-4-yl)pentyl]-2-pyrrolidinecarboxylic acid;
N-1-[5-(2-3-[Amino(imino)methyl]phenyl-3-oxo-2,3-dihydro-4H-1,4-benzothiazin-4-yl)pentyl]tetrahydro-1H-pyrrol-3-yl-N-methylacetamide;
3-4-[5-(3-Amino-1-pyrrolidinyl)pentyl]-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-ylbenzenecarboximidamide;
3-(4-5-[2,5-Bis(methoxymethyl)-1-pyrrolidinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)benzenecarboximidamide;
3-(4-5-[2-(Hydroxymethyl)-1-pyrrolidinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)benzenecarboximidamide;
3-(4-5-[2-(Hydroxymethyl)-5-methyl-1-pyrrolidinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)benzenecarboximidamide;
3-4-[5-(Diisopropylamino)pentyl]-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-ylbenzenecarboximidamide;
3-4-[5-(Diethylamino)pentyl]-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-ylbenzenecarboximidamide;
3-4-[5-(Methylamino)pentyl]-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-ylbenzenecarboximidamide;
3-4-[5-(1-Methyl-1H-imidazol-2-yl)pentyl]-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-ylbenzenecarboximidamide;
3-4-[5-(2,5-Dimethyl-1H-imidazol-1-yl)pentyl]-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-ylbenzenecarboximidamide;
3-[4-(5-Morpholinopentyl)-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl]benzenecarboximidamide;
3-4-[5-(3,5-Dimethylmorpholino)pentyl]-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-ylbenzenecarboximidamide;
3-[3-Oxo-4-(5-piperazinopentyl)-3,4-dihydro-2H-1,4-benzothiazin-2-yl]benzenecarboximidamide;
3-4-[5-(2,6-Dimethylpiperazino)pentyl]-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-ylbenzenecarboximidamide;
3-3-Oxo-4-[5-(1H-pyrazol-1-yl)pentyl]-3,4-dihydro-2H-1,4-benzothiazin-2-ylbenzenecarboximidamide;
3-[3-Oxo-4-(5-tetrahydro-1H-pyrazol-1-ylpentyl)-3,4-dihydro-2H-1,4-benzothiazin-2-yl]benzenecarboximidamide;
3-4-[5-(2,5-Dimethyltetrahydro-1H-pyrazol-1-yl)pentyl]-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-ylbenzenecarboximidamide;
3-(6-Chloro-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)benzenecarboximidamide;
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-6-fluoro-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)benzenecarboximidamide;
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-6-sulfanyl-3,4-dihydro-2H-1,4-benzothiazin-2-yl)benzenecarboximidamide;
3-[4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-6-(methylsulfanyl)-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl]benzenecarboximidamide;
3-[4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-6-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzothiazin-2-yl]benzenecarboximidamide;
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-6-methyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)benzenecarboximidamide;
2-3-[Amino(imino)methyl]phenyl-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazine-6-carboxylic acid;
Methyl 2-3-[amino(imino)methyl]phenyl-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazine-6-carboxylate;
3-(6-Cyano-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)benzenecarboximidamide;
2-3-[Amino(imino)methyl]phenyl-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazine-6-carboximidamide;
2-3-[amino(imino)methyl]phenyl-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-N-hydroxy-3-oxo-3,4-dihydro-2H-1,4-benzothiazine-6-carboximidamide;
3-4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-6-[hydrazino(imino)methyl]-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-ylbenzenecarboximidamide;
2-3-[Amino(imino)methyl]phenyl-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazine-6-carboxamide;
3-[4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-6-(hydroxymethyl)-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl]benzenecarboximidamide;
3-(6-(Aminomethyl)-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)benzenecarboximidamide;
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-6-nitro-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)benzenecarboximidamide;
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-6-hydroxy-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)benzenecarboximidamide;
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-6-methoxy-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)benzenecarboximidamide;
3-(6-(Benzyloxy)4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)benzenecarboximidamide;
2-[(2-3-[Amino(imino)methyl]phenyl-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-6-yl)oxy]acetic acid;
3-[(2-3-[Amino(imino)methyl]phenyl-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-6-yl)oxy]propanoic acid;
4-[(2-3-[Amino(imino)methyl]phenyl-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-6-yl)oxy]butanoic acid;
2-[(2-3-[Amino(imino)methyl]phenyl-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-6-yl)amino]acetic acid;
3-[(2-3-[Amino(imino)methyl]phenyl-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-6-yl)amino]propanoic acid;
4-[(2-3-[Amino(imino)methyl]phenyl-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-6-yl)amino]butanoic acid;
3-[4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-6-(2-hydroxyethoxy)-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl]benzenecarboximidamide;
3-[4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-6-(2H-1,2,3,4-tetraazol-5-ylmethoxy)-3,4-dihydro-2H-1,4-benzothiazin-2-yl]benzenecarboximidamide;
3-(6-Amino4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)benzenecarboximidamide;
3-(6-(Butylamino)-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)benzenecarboximidamide;
3-(6-(Dimethylamino)-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)benzenecarboximidamide;
3-(6-Anilino-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)benzenecarboximidamide;
3-(6-(Benzylamino)-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)benzenecarboximidamide;
N-(2-3-[Amino(imino)methyl]phenyl-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-6-yl)acetamide;
N-(2-3-[Amino(imino)methyl]phenyl-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-6-yl)cyclohexanecarboxamide;
N-(2-3-[Amino(imino)methyl]phenyl-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-6-yl)-2-cyclohexylacetamide;
N-(2-3-[Amino(imino)methyl]phenyl-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-6-yl)benzenecarboxamide;
N-(2-3-[Amino(imino)methyl]phenyl-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-6-yl)-2-phenylacetamide;
3-4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-6-[(methylsulfonyl)amino]-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-ylbenzenecarboximidamide;
3-(6-[(Cyclohexylsulfonyl)amino]-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)benzenecarboximidamide;
3-(6-[(Cyclohexylmethyl)sulfonyl]amino-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)benzenecarboximidamide;
3-4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-6-[(phenylsulfonyl)amino]-3,4-dihydro-2H-1,4-benzothiazin-2-ylbenzenecarboximidamide;
3-(6-[(Benzylsulfonyl)amino]-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)benzenecarboximidamide;
3-(4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)-4-methoxybenzenecarboximidamide;
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)benzenecarboximidamide;
4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-(3-hydroxyphenyl)-2H-1,4-benzoxazin-3(4H)-one;
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)-N-hydroxybenzenecarboximidamide;
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)benzenecarboximidohydrazide;
2-[3-(Aminomethyl)phenyl]-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2H-1,4-benzoxazin-3(4H)-one;
2-(3-Aminophenyl)-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2H-1,4-benzoxazin-3(4H)-one;
4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-[3-(methylamino)phenyl]-2H-1,4-benzoxazin-3(4H)-one;
2-[3-(Dimethylamino)phenyl]-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2H-1,4-benzoxazin-3(4H)-one;
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)-4-hydroxybenzenecarboximidamide;
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)tetrahydro-1(2H)-pyridinecarboximidamide;
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)-1-pyrrolidinecarboximidamide;
5-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)-2-thiophenecarboximidamide;
5-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)-2-furancarboximidamide;
2-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)-1,3-oxazole-5-carboximidamide;
5-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)-1,3-oxazole-2-carboximidamide;
4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-(1H-pyrazol-5-yl)-2H-1,4-benzoxazin-3(4H)-one;
4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-tetrahydro-1H-pyrazol-3-yl-2H-1,4-benzoxazin-3(4H)-one;
5-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)-1-pyrazolidinecarboximidamide;
4-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)-1H-imidazole-2-carboximidamide;
2-(2-Amino-1H-imidazol-4-yl)-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2H-1,4-benzoxazin-3(4H)-one;
2-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)-1H-imidazole-5-carboximidamide;
2-(5-Amino-1H-imidazol-2-yl)-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2H-1,4-benzoxazin-3(4H)-one;
4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-(3-pyridinyl)-2H-1,4-benzoxazin-3(4H)-one;
2-(4-Amino-3-pyridinyl)-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H-pyridinyl]pentyl-2H-1,4-benzoxazin-3(4H)-one;
2-[4-(Dimethylamino)-3-pyridinyl]-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2H-1,4-benzoxazin-3(4H)-one;
2-(6-Amino-2-pyridinyl)-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2H-1,4-benzoxazin-3(4H)-one;
6-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H1)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)-2-pyridinecarboximidamide;
2-(2-Amino-4-pyridinyl)-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2H-1,4-benzoxazin-3(4H)-one;
4-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)-2-pyridinecarboximidamide;
4-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)-2-pyrimidinecarboximidamide;
2-(2-Amino-4-pyrimidinyl)-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2H-1,4-benzoxazin-3(4H)-one;
2-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)-4-pyrimidinecarboximidamide;
2-(4-Amino-2-pyrimidinyl)-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2H-1,4-benzoxazin-3(4H)-one;
6-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)-2-pyrazinecarboximidamide;
2-(6-Amino-2-pyrazinyl)-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2H-1,4-benzoxazin-3(4H)-one;
4-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)-1,3,5-triazine-2-carboximidamide;
2-(4-Amino-1,3,5-triazin-2-yl)-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2H-1,4-benzoxazin-3(4H)-one;
5-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)-1,2,4-triazine-3-carboximidamide;
2-(3-Amino-1,2,4-triazin-5-yl)-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2H-1,4-benzoxazin-3(4H)-one;
3-[(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methyl]benzenecarboximidamide;
2-(3-Aminobenzyl)-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2H-1,4-benzoxazin-3(4H)-one;
2-[3-(Aminomethyl)benzyl]-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2H-1,4-benzoxazin-3(4H)-one;
3-[(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methyl]tetrahydro-1(2H)-pyridinecarboximidamide;
3-[(4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methyl]-1-pyrrolidinecarboximidamide;
5-[(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methyl]-2-thiophenecarboximidamide;
5-[(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methyl]-2-furancarboximidamide;
2-[(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methyl]-1,3-oxazole-5-carboximidamide;
5-[(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methyl]-1H-imidazole-2-carboximidamide;
2-[(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methyl]-1H-imidazole-5-carboximidamide;
6-[(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methyl]-2-pyridinecarboximidamide;
2-[(6-Amino-2-pyridinyl)methyl]-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2H-1,4-benzoxazin-3(4H)-one;
4-[(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methyl]-2-pyrimidinecarboximidamide;
2-[(2-Amino-4-pyrimidinyl)methyl]-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2H-1,4-benzoxazin-3(4H)-one;
2-[(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methyl]-4-pyrimidinecarboximidamide;
2-[(4-Amino-2-pyrimidinyl)methyl]-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2H-1,4-benzoxazin-3(4H)-one;
6-[(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methyl]-2-pyrazinecarboximidamide;
2-[(6-Amino-2-pyrazinyl)methyl]-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2H-1,4-benzoxazin-3(4H)-one;
2-(3-Aminocyclohexyl)-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2H-1,4-benzoxazin-3(4H)-one;
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)cyclohexanecarboximidamide;
2-[(3-Aminocyclohexyl)methyl]-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2H-1,4-benzoxazin-3(4H)-one;
3-[(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methyl]cyclohexanecarboximidamide;
2-(3-Aminocyclopentyl)-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2H-1,4-benzoxazin-3(4H)-one;
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)cyclopentanecarboximidamide;
2-[(3-Aminocyclopentyl)methyl]-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2H-1,4-benzoxazin-3(4H)-one;
3-[(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methyl]cyclopentanecarboximidamide;
3-(4-4-[(2R,6S)-2,6-Dimethyltetrahydro-1(2h)-pyridinyl]butyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)benzenecarboximidamide;
3-(4-6-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]hexyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)benzenecarboximidamide;
2-(2-3-[Amino(imino)methyl]phenyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-N-2-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]ethylacetamide;
3-(2-3-[Amino(imino)methyl]phenyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-N-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]methylpropanamide;
3-4-[2-(2-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]ethylamino)ethyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-ylbenzenecarboximidamide;
3-[4-(2-2-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]ethoxyethyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl]benzenecarboximidamide;
3-(4-4-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]phenyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)benzenecarboximidamide;
3-(4-4-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]benzyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)benzenecarboximidamide;
3-[4-(4-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]methylphenyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl]benzenecarboximidamide;
3-(4-4-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]cyclohexyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)benzenecarboximidamide;
3-[4-(4-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]cyclohexylmethyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl]benzenecarboximidamide;
3-[4-(4-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]methylcyclohexyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl]benzenecarboximidamide;
3-(4-3-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]cyclopentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)benzenecarboximidamide;
3-[4-(3-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]cyclopentylmethyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl]benzenecarboximidamide;
3-[4-(3-[(2R,6S)-2,6-Dimethvltetrahydro-1(2H)-pyridinyl]methylcyclopentyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl]benzenecarboximidamide;
3-(4-(E)-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]-2-pentenyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)benzenecarboximidamide;
3-[3-Oxo-4-(5-piperidinopentyl)-3,4-dihydro-2H-1,4-benzoxazin-2-yl]benzenecarboximidamide;
3-3-Oxo-4-[5-(2,2,6,6-tetramethylpiperidino)pentyl]-3,4-dihydro-2H-1,4-benzoxazin-2-ylbenzenecarboximidamide;
1-[5-(2-3-[Amino(imino)methyl]phenyl-3-oxo-2,3-dihydro4H-1,4-benzoxazin-4-yl)pentyl]-2-piperidinecarboxylic acid;
1-[5-(2-3-[Amino(imino)methyl]phenyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)pentyl]-3-piperidinecarboxylic acid;
1-[5-(2-3-[Amino(imino)methyi]phenyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)pentyl]-4-piperidinecarboxylic acid;
3-4-[5-(3,5-Dimethylpiperidino)pentyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-ylbenzenecarboximidamide;
3-4-[5-(4-Hydroxypiperidino)pentyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-ylbenzenecarboximidamide;
3-4-[5-(2-Iminopiperidino)pentyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-ylbenzenecarboximidamide;
3-3-Oxo-4-[5-(4-oxopiperidino)pentyl]-3,4-dihydro-2H-1,4-benzoxazin-2-ylbenzenecarboximidamide;
3-[4-(5-2-[(Dimethylamino)methyl]piperidinopentyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl]benzenecarboximidamide;
3-(4-5-[4-(Dimethylamino)piperidino]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)benzenecarboximidamide;
1-[5-(2-3-[Amino(imino)methyl]phenyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)pentyl]-4-piperidinesulfonic acid;
3-3-Oxo-4-[5-(2-phenylpiperidino)pentyl]-3,4-dihydro-2H-1,4-benzoxazin-2-ylbenzenecarboximidamide;
3-4-[5-(2,5-Dimethyl-1-pyrrolidinyl)pentyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-ylbenzenecarboximidamide;
3-3-Oxo-4-[5-(1-pyrrolidinyl)pentyl]-3,4-dihydro-2H-1,4-benzoxazin-2-ylbenzenecarboximidamide;
1-[5-(2-3-[Amino(imino)methyl]phenyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)pentyl]-2-pyrrolidinecarboxylic acid;
N-1-[5-(2-3-[Amino(imino)methyl]phenyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)pentyl]tetrahydro-1H-pyrrol-3-yl-N-methylacetamide;
3-4-[5-(3-Amino-1-pyrrolidinyl)pentyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-ylbenzenecarboximidamide;
3-(4-5-[2,5-Bis(methoxymethyl)-1-pyrrolidinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)benzenecarboximidamide;
3-(4-5-[2-(Hydroxymethyl)-1-pyrrolidinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)benzenecarboximidamide;
3-(4-5-[2-(Hydroxymethyl)-5-methyl-1-pyrrolidinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)benzenecarboximidamide;
3-4-[5-(Diisopropylamino)pentyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-ylbenzenecarboximidamide;
3-4-[5-(Diethylamino)pentyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-ylbenzenecarboximidamide;
3-4-[5-(Methylamino)pentyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-ylbenzenecarboximidamide;
3-4-[5-(1-Methyl-1H-imidazol-2-yl)pentyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-ylbenzenecarboximidamide;
3-4-[5-(2,5-Dimethyl-1H-imidazol-1-yl)pentyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-ylbenzenecarboximidamide;
3-[4-(5-Morpholinopentyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl]benzenecarboximidamide;
3-4-[5-(3,5-Dimethylmorpholino)pentyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-ylbenzenecarboximidamide;
3-[3-Oxo-4-(5-piperazinopentyl)-3,4-dihydro-2H-1,4-benzoxazin-2-yl]benzenecarboximidamide;
3-4-[5-(2,6-Dimethylpiperazino)pentyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-ylbenzenecarboximidamide;
3-3-Oxo-4-[5-(1H-pyrazol-1-yl)pentyl]-3,4-dihydro-2H-1,4-benzoxazin-2-ylbenzenecarboximidamide;
3-[3-Oxo-4-(5-tetrahydro-1H-pyrazol-1-ylpentyl)-3,4-dihydro-2H-1,4-benzoxazin-2-yl]benzenecarboximidamide;
3-4-[5-(2,5-Dimethyltetrahydro-1H-pyrazol-1-yl)pentyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-ylbenzenecarboximidamide;
3-(6-Chloro-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)benzenecarboximidamide;
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-6-fluoro-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)benzenecarboximidamide;
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-6-sulfanyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)benzenecarboximidamide;
3-[4-5-[(2R,6S)-26-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-6-(methylsulfanyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl]benzenecarboximidarmide;
3-[4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-6-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-2-yl]benzenecarboximidamide;
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-6-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)benzenecarboximidamide;
2-3-[Amino(imino)methyl]phenyl-4-5-[(2R,6S)-2.6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylic acid;
Methyl 2-3-[amino(imino)methyl]phenyl-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate;
3-(6-Cyano-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)benzenecarboximidamide;
2-3-[Amino(imino)methyl]phenyl4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboximidamide;
2-3-[Amino(imino)methyl]phenyl-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-N-hydroxy-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboximidamide;
3-4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-6-[hydrazino(imino)methyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-ylbenzenecarboximidamide;
2-3-[Amino(imino)methyl]phenyl-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxamide;
3-[4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-6-(hydroxymethyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl]benzenecarboximidamide;
3-(6-(Aminomethyl)-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)benzenecarboximidamide;
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-6-nitro-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)benzenecarboximidamide;
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2h)-pyridinyl]pentyl-6-hydroxy-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)benzenecarboximidamide;
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-6-methoxy-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)benzenecarboximidamide;
3-(6-(Benzyloxy)-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)benzenecarboximidamide;
2-[(2-3-[Amino(imino)methyl]phenyl-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)oxy]acetic acid
3-[(2-3-[Amino(imino)methyl]phenyl-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)oxy]propanoic acid;
4-[(2-3-[Amino(imino)methyl]phenyl-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)oxy]butanoic acid;
2-[(2-3-[Amino(imino)methyl]phenyl4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)amino]acetic acid;
3-[(2-3-[Amino(imino)methyl]phenyl-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)amino]propanoic acid;
4-[(2-3-[Amino(imino)methyl]phenyl-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)amino]butanoic acid;
3-[4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-6-(2-hydroxyethoxy)-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl]benzenecarboximidamide;
3-[4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-6-(2H-1,2,3,4-tetraazol-5-ylmethoxy)-3,4-dihydro-2H-1,4-benzoxazin-2-yl]benzenecarboximidamide;
3-(6-Amino4-5-[(2R,6S)-2.6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)benzenecarboximidamide;
3-(6-(Butylamino)-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)benzenecarboximidamide;
3-(6-(Dimethylamino)-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)benzenecarboximidamide;
3-(6-Anilino-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)benzenecarboximidamide;
3-(6-(Benzylamino)-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)benzenecarboximidamide;
N-(2-3-[Amino(imino)methyl]phenyl-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)acetamide;
N-(2-3-[Amino(imino)methyl]phenyl-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)cyclohexanecarboxamide;
N-(2-3-[Amino(imino)methyl]phenyl-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)-2-cyclohexylacetamide;
N-(2-3-[Amino(imino)methyl]phenyl-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)benzenecarboxamide;
N-(2-3-[Amino(imino)methyl]phenyl4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)-2-phenylacetamide;
3-4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-6-[(methylsulfonyl)amino]-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-ylbenzenecarboximidamide;
3-(6-[(Cyclohexylsulfonyl)amino]-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)benzenecarboximidamide;
3-(6-[(Cyclohexylmethyl)sulfonyl]amino-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)benzenecarboximidamide;
3-4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-6-[(phenyisulfonyl)amino]-3,4-dihydro-2H-1,4-benzoxazin-2-ylbenzenecarboximidamide;
3-(6-[(Benzylsulfonyl)amino]-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)benzenecarboximidamide;
2H-1,4-Benzoxazin-3(4H)-one, 4-[3-(2,6-dimethyl-1-piperidinyl)propyl]-2-phenyl-;
4-[5-(2,5-Dimethyl-pyrrolidin-1-yl)-pentyl]-2-phenyl-4H-benzo[1,4]oxazin-3-one;
2H-1,4-Benzoxazin-3(4H)-one, 4-[5-[bis(1-methylethyl)amino]pentyl]-2-phenyl-;
2H-1,4-Benzoxazin-3(4H)-one, 4-[3-(2,5-dimethyl-1-pyrrolidinyl)propyl]-2-phenyl-;
2H-1,4-Benzoxazin-3(4H)-one, 4-[3-[bis(1-methylethyl)amino]propyl]-2-phenyl-;
4-[5-(2,6-Dimethyl -piperidin-1-yl)-pentyl]-2-phenyl-4H-benzo[1,4]oxazin-3-one; 4-(5-Diethylamino-pentyl)-2-phenyl-4H-benzo[1,4]oxazin-3-one;
2-Phenyl-4-(5-pyrrolidin-1-yl-pentyl)-4H-benzo[1,4]oxazin-3-one;
2-[5-(3-Oxo-2-phenyl-2,3-dihydro-benzo[1,4]oxazin-4-yl)-pentyl]-isoindole-1,3-dione;
4-(5-Imidazol-1-yl-pentyl)-2-phenyl-4H-benzo[1,4]oxazin-3-one;
2-(4-Chloro-phenyl)-4-[5-(2,6-dimethyl-piperidin-1-yl)-pentyl]-4H-benzo[1,4]oxazin-3-one;
2-(2-Chloro-phenyl)-4-[5-(2,5-dimethyl-pyrrolidin-1-yl)-pentyl]-4H-benzo[1,4]oxazin-3-one;
2-(2-Chloro-phenyl)-4-[5-(2,6-dimethyl-piperidin-1-yl)-pentyl]-4H-benzo[1,4]oxazin-3-one;
5-(3-Oxo-2-phenyl-2,3-dihydro-benzo[1,4]oxazin-4-yl)-pentanamidine;
2-Phenyl-4-(5-piperidin-1-yl-pentyl)-4H-benzo[1,4]oxazin-3-one;
2-(4-Chloro-phenyl)-4-[5-(2,5-dimethyl-pyrrolidin-1-yl)-pentyl]-4H-benzo[1,4]oxazin-3-one;
2-Phenyl4-(5-pyrrolidin-1-yl-pentyl)-4H-benzo[1,4]oxazin-3-one; compound with trifluoro-acetic acid;
3-(3-Oxo-2-phenyl-2,3-dihydro-benzo[1,4]oxazin-4-ylmethyl)-benzonitrile;
4-[6-(2,5-Dimethyl-pyrrolidin-1-yl)-hexyl]-2-phenyl-4H-benzo[1,4]oxazin-3-one;
3-(3-Oxo-2-phenyl-2,3-dihydro-benzo[1,4]oxazin-4-ylmethyl)-benzamidine;
2-Naphthalen-2-yl-4-(5-piperidin-1-yl-pentyl)-4H-benzo[1,4]oxazin-3-one;
4-(5-Amino-pentyl)-2-phenyl-4H-benzo[1,4]oxazin-3-one;
4-[5-(2,6-Dimethyl-piperidin-1-yl)-pentyl]-2-phenyl-4H-benzo[1,4]oxazin-3-one;
6-Methyl-2-phenyl-4-(5-piperidin-1-yl-pentyl)-4H-benzo[1,4]oxazin-3-one;
7-Methoxy-2-phenyl-4-(5-piperidin-1-yl-pentyl)-4H-benzo[1,4]oxazin-3-one;
8-Chloro-2-phenyl-4-(5-piperidin-1-yl-pentyl)-4H-benzo[1,4]oxazin-3-one;
3-Oxo-2-phenyl-4-(5-piperidin-1-yl-pentyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonitrile;
4-(3-Oxo-2-phenyl-2,3-dihydro-benzo[1,4]oxazin-4-ylmethyl)-benzamidine;
1-[5-(3-Oxo-2-phenyl-2,3-dihydro-benzo[1,4]oxazin-4-yl)-pentyl]-piperidine-2,6-dione;
3-(3-Oxo-2-phenyl-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionitrile;
4-(3-Oxo-2-phenyl-2,3-dihydro-benzo[1,4]oxazin-4-yl)-butyronitrile;
5-(3-Oxo-2-phenyl-2,3-dihydro-benzo[1,4]oxazin-4-yl)-pentanenitrile;
N-[3-(3-Oxo-2-phenyl-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propyl]-guanidine;
N-[5-(3-Oxo-2-phenyl-2,3-dihydro-benzo[1,4]oxazin-4-yl)-pentyl]-guanidine;
4-(3-Oxo-2-phenyl-2,3-dihydro-benzo[1,4]oxazin-4-ylmethyl)-benzamidine;
2-(4-Methoxy-phenyl)-4-(5-piperidin-1-yl-pentyl)-4H-benzo[1,4]oxazin-3-one;
7-Methyl-2-phenyl-4-(5-piperidin-1-yl-pentyl)-4H-benzo[1,4]oxazin-3-one;
5-Methyl-2-phenyl-4-(5-piperidin-1-yl-pentyl)-4H-benzo[1,4]oxazin-3-one;
6-Methoxy-2-phenyl-4-(5-piperidin-1-yl-pentyl)-4H-benzo[1,4]oxazin-3-one;
N-Hydroxy-4-(3-oxo-2-phenyl-2,3-dihydro-benzo[1,4]oxazin-4-ylmethyl)-benzamidine;
6-Chloro-2-phenyl-4-(5-piperidin-1-yl-pentyl)-4H-benzo[1,4]oxazin-3-one;
2-(4-Methoxy-phenyl)-4-(5-piperazin-1-yl-pentyl)-4H-benzo[1,4]oxazin-3-one;
2-(4-Hydroxy-phenyl)-4-(5-piperidin-1-yl-pentyl)-4H-benzo[1,4]oxazin-3-one;
4-[5-(2,6-Dimethyl-piperidin-1-yl)-pentyl]-2-(4-hydroxy-phenyl)-4H-benzo[1,4]oxazin-3-one;
2-(4-Methoxy-phenyl)-4-[5-(4-methyl-piperazin-1-yl)-pentyl]-4H-benzo[1,4]oxazin-3-one;
4-{4-[5-(2,6-Dimethyl-piperidin-1-yl)-pentyl]-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl}-benzonitrile;
4-{4-[5-(2,6-Dimethyl-piperidin-1-yl)-pentyl]-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl}-benzamidine;
4-{4-[5-(2,6-Dimethyl-piperidin-1-yl)-pentyl]-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl}-thiobenzamide;
[2-(4-Methoxy-phenyl)-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl]-acetic acid;
4-{4-[5-(2,6-Dimethyl-piperidin-1-yl)-pentyl]-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl}-N-hydroxy-benzamidine;
Benzenecarboximidic acid, 4-[3,4-dihydro-4-[5-(2,6-dimethyl-1-piperidinyl)pentyl]-3-oxo-2H-1,4-benzoxazin-2-yl]-, hydrazide;
6-Amino-2-phenyl-4-(5-piperidin-1-yl-pentyl)-4H-benzo[1,4]oxazin-3-one;
4-(5-Bromo-pentyl)-2-(3,4-dimethoxy-phenyl)-4H-benzo[1,4]oxazin-3-one;
4-(5-Bromo-pentyl)-2-(3,4,5-trimethoxy-phenyl)-4H-benzo[1,4]oxazin-3-one;
4-(5-Bromo-pentyl)-2-(4-methoxy-phenyl)-4H-benzo[1,4]oxazin-3-one;
N-[2-(2,6-Dimethyl-piperidin-1-yl)-ethyl]-2-[2-(4-methoxy-phenyl)-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl]-acetamide;
4-[5-(2,6-Dimethyl-piperidin-1-yl)-pentyl]-2-(3,4,5-trimethoxy-phenyl)-4H-benzo[1,4]oxazin-3-one;
2-(3,4-Dimethoxy-phenyl)-4-[5-(2,6-dimethyl-piperidin-1-yl)-pentyl]-4H-benzo[1,4]oxazin-3-one;
2-(4-Bromo-phenyl)-4-[5-(2,6-dimethyl-piperidin-1-yl)-pentyl]-4H-benzo[1,4]oxazin-3-one;
8-Methyl-2-phenyl-4-(5-piperidin-1-yl-pentyl)-4H-benzo[1,4]oxazin-3-one;
2-(4-Benzylamino-phenyl)-4-[5-(2,6-dimethyl-piperidin-1-yl)-pentyl]4H-benzo[1,4]oxazin-3-one;
2-(4-Methoxy-phenyl)-4-[5-(2,2,6,6-tetramethyl-piperidin-1-yl)-pentyl]-4H-benzo[1,4]oxazin-3-one;
4-(2-Bromo-ethyl)-2-(4-methoxy-phenyl)-4H-benzo[1,4]oxazin-3-one;
4-(5-Bromo-pentyl)-2-(3,4-dichloro-phenyl)-4H-benzo[1,4]oxazin-3-one;
4-(2-Hydroxy-ethyl)-2-(4-methoxy-phenyl)-4H-benzo[1,4]oxazin-3-one;
2-(3,4-Dichloro-phenyl)-4-[5-(2,6-dimethyl-piperidin-1-yl)-pentyl]-4H-benzo[1,4]oxazin-3-one;
4-[3-(2,6-Dimethyl-piperidin-1-ylmethyl)-benzyl]-2-(4-methoxy-phenyl)-4H-benzo[1,4]oxazin-3-one;
4-(2-Amino-ethyl)-2-(4-methoxy-phenyl)4H-benzo[1,4]oxazin-3-one;
2-(2,6-Dimethyl-piperidin-1-yl)-N-{2-[2-(4-methoxy-phenyl)-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl]-ethyl}-acetamide;
4-[5-(2,6-Dimethyl-piperidin-1-yl)-5-oxo-pentyl]-2-(4-methoxy-phenyl)-4H-benzo[1,4]oxazin-3-one;
3-{4-[4-(2,6-Dimethyl-piperidin-1-yl)-butyl]-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl}-benzamidine;
3-{4-[6-(2,6-Dimethyl-piperidin-1-yl)-hexyl]-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl}-benzamidine;
2-(5-Aminomethyl-2-hydroxy-phenyl)-4-[5-(2,6-dimethyl-piperidin-1-yl)-pentyl]-4H-benzo[1,4]oxazin-3-one;
2-(3-Aminomethyl-phenyl)-4-[5-(2,6-dimethyl-piperidin-1-yl)-pentyl]4H-benzo[1,4]oxazin-3-one;
3-{4-[5-(2,6-Dimethyl-piperidin-1-yl)-pentyl]-7-methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl}-benzamidine;
3-{4-[5-(2,6-Dimethyl-piperidin-1-yl)-pentyl]-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl}-4-methoxy-benzamidine;
2-(5-Aminomethyl-2-methoxy-phenyl)-4-[5-(2,6-dimethyl-piperidin-1-yl)-pentyl]-4H-benzo[1,4]oxazin-3-one;
3-{4-[5-(2,6-Dimethyl-piperidin-1-yl)-pentyl]-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl}-N-hydroxy-4-methoxy-benzamidine;
3-{4-[5-(2,6-Dimethyl-piperidin-1-yl)-pentyl]-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl}-N-hydroxy-benzamidine;
3-{7-Chloro-4-[5-(2,6-dimethyl-piperidin-1-yl)-pentyl]-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl}-benzamidine;
4-(5-Bromo-pentyl)-2-phenyl-4H-benzo[1,4]oxazin-3-one;
3-[3-Oxo-4-(5-piperidin-1-yl-pentyl)-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl]-benzamidine;
N-{2-(3-Carbamimidoyl-phenyl)-4-[5-(2,6-dimethyl-piperidin-1-yl)-pentyl]-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl}-acetamide;
3-{4-[5-(2,6-Dimethyl-piperidin-1-yl)-pentyl]-2-methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl}-4-hydroxy-benzamidine;
3-[4-(5-Diisopropylamino-pentyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl]-benzamidine;
3-(4-{4-[(Diisopropylamino)-methyl]-benzyl}-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-benzamidine;
3-{4-[4-(2,6-Dimethyl-piperidin-1-ylmethyl)-benzyl]-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl}-benzamidine;
3-{4-[5-(2,6-Dimethyl-piperidin-1-yl)-pentyl]-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl}-4-hydroxy-benzamidine;
3-{4-[5-(2,6-Dimethyl-piperidin-1-yl)-pentyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl}-N-methyl-benzamidine;
{2-(3-Carbamimidoyl-phenyl)-4-[5-(2,6-dimethyl-piperidin-1-yl)-pentyl]-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl}-acetic acid;
3-(4-{3-[(Diisopropylamino)-methyl]-benzyl}-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-benzamidine;
3-{4-[3-(2,6-Dimethyl-piperidin-1-ylmethyl)-benzyl]-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl}-benzamidine;
2-(3-Carbamimidoyl-phenyl)-4-[5-(2,6-dimethyl-piperidin-1-yl)-pentyl]-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-7-carboxylic acid;
3-{-Oxo-4-[4-(pyridin-2-ylmino)-butyl]-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl}-benzamidine;
2-(3-Carbamimidoyl-phenyl)-4-(5-(2,6-dimethyl-piperidin-1-yl)-pentyl]-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-7-carboxylic acid methyl ester;
3-[4-(5-Dihexylamino-pentyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl]-benzamidine;
3-{4-[4-(Methyl-pyridin-2-yl-amino)-butyl]-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl}-benzamidine;
4-[5-(2,6-Dimethyl-piperidin-1-yl)-pentyl]-2-[3-(imino-morpholin-4-yl-methyl)-phenyl]-4H-benzo[1,4]oxazin-3-one;
3-{3-Oxo-4-[4-(pyrimidin-2-ylamino)-butyl]-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl}-benzamidine;
3-[4-(4-Cyclohexylamino-butyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl]-benzamidine;
3-{4-[5-(2,5-Dimethyl-pyrrolidin-1-yl)-pentyl]-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl}-benzamidine;
3-[4-(5-Morpholin-4-yl-pentyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl]-benzamidine;
3-{4-[5-(2,6-Dimethyl-piperidin-1-yl)-2,3-dihydroxy-pentyl]-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl}-benzamidine;
4-[2-(3-Carbamimidoyl-phenyl)-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-ylmethyl]-N,N-dimethyl-benzamide;
2-(3-Carbamimidoyl-phenyl)4-[5-(2,6-dimethyl-piperidin-1-y)-pentyl]-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid;
3-[2-(3-Carbamimidoyl-phenyl)-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-ylmethyl]-N,N-dimethyl-benzamide;
3-{4-[5-(2,6-Dimethyl-piperidin-1-yl)-pent-2-enyl]-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl}-benzamidine;
3-[4-(5-Amino-pentyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl]-benzamidine;
2-(3-Carbamimidoyl-phenyl)-4-[5-(2,6-dimethyl-piperidin-1-yl)-pentyl]-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid methyl ester;
4-Methoxy-3-[4-(4-methoxy-benzyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl]-benzonitrile;
3-{4-[5-(2,6-Dimethyl-piperidin-1-yl)-pent-3-enyl]-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl}-benzamidine;
4-[2-(3-Cyano-phenyl)-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-ylmethyl]-N,N-dimethyl-benzamide;
3-[2-(3-Carbamimidoyl-phenyl)-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-ylmethyl]-5-(2,6-dimethyl-piperidin-1-ylmethyl)-benzoic acid;
3-{4-[5-(2,6-Dimethyl-piperidin-1-yl)-pentyl]-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl}-4-hydroxy-benzamidine;
3-Acetyl-2-(2-methoxy-phenyl)-thiazolidine4-carboxylic acid 4-cyano-2-{4-[5-(2,6-dimethyl-piperidin-1-yl)-pentyl]-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl}-phenyl ester;
3-[2-(3-Carbamimidoyl-phenyl)-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-ylmethyl]-5-(2,6-dimethyl-piperidin-1-ylmethyl)-N-hydroxy-benzamide;
4-(2-Dimethylamino-ethyl)-7-nitro-2-phenyl-4H-benzo[1,4]thiazin-3-one;
4-(2-Diethylamino-ethyl)-7-nitro-2-phenyl-4H-benzo[1,4]thiazin-3-one;
2H-1,4-Benzothiazin-3(4H)-one, 4-[2-(dimethylamino)ethyl]-7-nitro-2-phenyl-, monohydrochloride;
2H-1,4-Benzothiazin-3(4H)-one, 4-[2-(diethylamino)ethyl]-7-nitro-2-phenyl-, monohydrochloride;
4-[5-(2,6-Dimethyl-piperidin-1-yl)-pentyl]-2-(4-methoxy-phenyl)-4H-benzo[1,4]thiazin-3-one;
4-{4-[5-(2,6-Dimethyl-piperidin-1-yl)-pentyl]-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-2-yl}-benzonitrile;
4-{4-[5-(2,6-Dimethyl-piperidin-1-yl)-pentyl]-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-2-yl}-thiobenzamide;
4-[5-(2,6-Dimethyl-piperidin-1-yl)-pentyl)-2-(4-methoxy-phenyl)-4H-benzo[1,4]thiazin-3-one; compound with trifluoro-acetic acid;
3-{4-[5-(2,6-Dimethyl-piperidin-1-yl)-pentyl]-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-2-yl}-benzonitrile;
3-{4-[5-(2,6-Dimethyl-piperidin-l-yl)-pentyl]-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-2-yl}-benzamide;
4-[5-(2,6-Dimethyl-piperidin-1-yl)-pentyl]-2-(3-methoxy-phenyl)-2-(4-methoxy-phenyl)-4H-benzo[1,4]thiazin-3-one;
4-[5-(2,6-Dimethyl-piperidin-1-yl)-pentyl]-2-(4-methoxy-phenyl)-1,1-dioxo-1,4-dihydro-2H-11 greater than 6-benzo[1,4]thiazin-3-one;
2-(4-Benzyloxy-phenyl)-4-[5-(2,6-dimethyl-piperidin-1-yl)-pentyl]4H-benzo[1,4]thiazin-3-one;
2-(4-Butoxy-phenyl)-4-[5-(2,6-dimethyl-piperidin-1-yl)-pentyl]-4H-benzo[1,4]thiazin-3-one;
3-{4-[5-(2,6-Dimethyl-piperidin-1-yl)-pentyl]-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-2-yl}-thiobenzamide;
4-{4-[5-(2,6-Dimethyl-piperidin-1-yl)-pentyl]-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-2-yl}-benzamidine;
3-{4-(5-(2,6-Dimethyl-piperidin-1-yl)-pentyl]-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-2-yl}-N-hydroxy-benzamidine;
3-{4-[5-(2,6-Dimethyl-piperidin-1-yl)-pentyl]-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-2-yl}-benzamidine;
3-{4-[5-(2-Hydroxymethyl-pyrrolidin-1-yl)-pentyl]-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-2-yl}-benzamidine;
4-Allyl-2,2-diphenyl-4H-benzo[1,4]thiazin-3-one;
4-(2-Diethylamino-ethyl)-7-nitro-2-phenyl-4H-benzo[1,4]thiazin-3-one;
2-(3-Diethylamino-propylamino)-4-methyl-2-phenyl-4H-benzo[1,4]thiazin-3-one;
4-(2-Diethylamino-ethyl)-2,2-diphenyl-4H-benzo[1,4]thiazin-3-one;
2-Benzyl-4-(5-piperidin-1-yl-pentyl)-4H-benzo[1,4]oxazin-3-one;
2-Cyclohexyl-4-[5-(2,6-dimethyl-piperidin-1-yl)-pentyl]-4H-benzo[1,4]thiazin-3-one;
2H-1,4-Benzothiazin-3(4H)-one, 4-methyl-2,2-diphenyl-;
4-Ethyl-2-phenyl-2-piperidin-1-yl-4H-benzo[1,4]thiazin-3-one;
4-Methyl-2-phenyl-2-piperidin-1-yl-4H-benzo[1,4]thiazin-3-one;
3-{4-[5-(2,6-dimethyl-piperidin-1-yl)-pentyl]-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl}-piperidine-1-carboxamidine;
4-[5-(2,6-Dimethyl-piperidin-1-yl)-pentyl]-2-piperidin-3-yl-4H-benzo[1,4]oxazin-3-one;
3-Oxo-2-phenyl-2,4-bis-(5-piperidin-1-yl-pentyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonitrile;
4-[5-(2,6-Dimethyl-piperidin-1-yl)-pentyl]-2-pyridin-2-yl-4H-benzo[1,4]oxazin-3-one;
N-Hydroxy-3-oxo-2-phenyl-4-(5-piperidin-1-yl-pentyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxamidine;
3-Oxo-2-phenyl-4-(5-piperidin-1-yl-pentyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxamidine;
3-{4-[5-(2,6-Dimethyl-piperidin-1-yl)-pentyl]-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl}-thiobenzamide;
3-{4-[5-(Adamantan-1-ylamino)-pentyl]-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl}-benzamidine;
2-(3-Diethylamino-propylamino)-4-methyl-2-phenyl-4H-benzo[1,4]oxazin-3-one;
4-[3-(2,6-Dimethyl-1-piperidinyl)propyl]-2-phenyl-2H/-1,4-benzoxazin-3(4H/)-one; and
4-Methyl-2-phenyl-2H/-1,4-benzoxazin-3(4H/)-one.
The term xe2x80x9calkylxe2x80x9d means a straight, branched, saturated or unsaturated carbon chain having from 1 to 20 carbon atoms. Typical alkyl groups include methyl, isobutyl, pentyl, 2-methyl-pentyl, pent-1,4-dienyl, but-1-enyl and the like.
The term xe2x80x9ccycloalkylxe2x80x9d means a saturated or unsaturated carbon chain which forms a ring having from 3 to 20 carbon atoms. Typical examples include cyclopropyl, cyclohexyl and the like.
The term xe2x80x9ccycloalkylalkylxe2x80x9d means a cycloalkyl group attached to an alkyl group wherein xe2x80x9ccycloalkylxe2x80x9d and xe2x80x9calkylxe2x80x9d are as defined above and includes, for example, cyclopropylmethyl, cyclopentylethyl and the like.
The term xe2x80x9cheteroalkylxe2x80x9d means a straight, branched, saturated or unsaturated carbon chain having from 1 to 20 carbon atoms wherein one or more carbon atoms is replaced by a heteroatom selected from oxygen, nitrogen, sulfur, sulphoxide or sulphone. Typical xe2x80x9cheteroalkylxe2x80x9d groups include methoxymethyl, 3-thiomethylpropyl, and 2-thiomethoxyethoxymethyl and the like.
The term xe2x80x9carylxe2x80x9d represents an unsaturated carbocyclic ring(s) of 6 to 16 carbon atoms which is optionally substituted with, OH, O(alkyl), SH, S(alkyl), amine, halogen, acid, ester, amide, alkyl ketone, aldehyde, nitrile, fluoroalkyl, amidine, nitro, sulphone. sulfoxide or (C1-6)alkyl, thioamide, Oalkylaryl, benzylamino, C(NH)(NHNH2), N-hydroxyamidine, N-methylamidine. Typical rings include phenyl, naphthyl, phenanthryl, and anthracenyl. Preferred aryl rings are phenyl, substituted phenyl, and naphthyl.
The term xe2x80x9carylalkylxe2x80x9d means an aromatic radical attached to an alkyl radical wherein xe2x80x9carylxe2x80x9d and xe2x80x9calkylxe2x80x9d are as defined above and includes, for example, benzyl, and naphthylmethyl.
The term xe2x80x9cheterocyclexe2x80x9d means a saturated or unsaturated mono- or polycyclic (i.e. bicyclic) ring incorporating one or more (i.e. 1-4) heteroatoms selected from N, O, and S. It is understood that a heterocycle is optionally substituted with OH, O(alkyl), SH, S(alkyl), amine, halogen, acid, ester, amide, amidine alkyl ketone, aldehyde, nitrile, fluoroalkyl, nitro, sulphone, sulfoxide or C1-6 alkyl. Examples of suitable monocyclic heterocycles include, but are not limited to substituted or unsubstituted thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, piperidinyl, pyrrolidinyl, piperazinyl, azetidinyl, aziridinyl, morpholinyl, thietanyl, oyetanyl. Preferred monoydicheterocycles include, but are not limited to, 2- or 3- thienyl, 2- or 3-furanyl, 1-, 2-, or 3-pyrrolyl, 1-, 2-, 4-, or 5-imidazolyl, 1-, 3-, 4-, or 5-pyrazolyl, 2-, 4-, or 5-thiazolyl, 3-, 4-, or 5-isothiazolyl, 2-, 4-, or 5-oxazolyl, 3-, 4-, or 5-isoxazolyl, 1, 3-, or 5-triazolyl, 1-, 2-, or 3-tetrazolyl, 2, 3-, or 4-pyridinyl, 2-pyrazinyl, 2-, 4-, or 5-pyrimidinyl, 1-, 2-, 3-, or 4- piperidinyl, 1-, 2-, or 3-pyrrolidinyl, 1- or 2-piperazinyl, 1-, 2-, or 3-azetidinyl, 1- or 2-aziridinyl, 2-, 3-, or 4-morpholinyl, 2- or 3- thietanyl, 2- or 3-oxetanyl. Examples of suitable bicyclic heterocycles include, but are not limited to, indolizinyl, isoindolyl, benzothienyl, benzoxazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, and preferably 1-, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 1-, 2-, 3-, 5-, 6-, 7-, or 8-indolizinyl, 1-, 2-, 3-, 4-, 5-, 6-, or 7-isoindolyl, 2-, 3-, 4-, 5-, 6-, or 7-benzothienyl, 2-, 4-, 5-, 6-, or 7-benzoxazolyl, 1-, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, 2-, 3-, 4-, 5-, 6-* 7-, or 8-quinolinyl, 1-3-, 4-, 5-, 6-, 7-, or 8-isoquinolinyl.
The term xe2x80x9cheteroatomxe2x80x9d as used herein represents oxygen. nitrogen, or sulfur (O, N, or S) as well as sulfoxyl or sulfonyl (SO or SO2) unless otherwise indicated. It is understood that alkyl chains interrupted by one or more heteroatoms means that a carbon atom of the chain is replaced with a heteroatom having the appropriate valency. Preferably, an alkyl chain is interrupted by 1 to 4 heteroatoms and that two adjacent carbon atoms are not both replaced. Examples of such groups include methoxymethyl, 3-thiomethylpropyl, and 2-thiomethoxyethoxymethyl.
The term xe2x80x9caminexe2x80x9d refers to a group such as NH2, NHalkyl, NH(cycloalkyl), NH(cycloalkylalkyl), NH(aryl), NH(arylalkyl), NH(heteroaryl), NH(heteroarylalkyl), N(alkyl)(alkyl), N(alkyl)(cycloalkyl), N(alkyl)(cycloalkylalkyl), N(alkyl)(aryl), N(alkyl)(arylalkyl), N(alkyl)(heteroaryl), N(alkyl)(heteroarylalkyl), N(cycloalkyl)(cycloalkyl), N(cycloalkyl)(cycloalkylalkyl), N(cycloalkyl)(aryl), N(cycloalkyl)(arylalkyl), N(cycloalkyl)(heteroaryl), N(cycloalkyl)(heteroarylalkyl), N(cycloalkylalkyl)(cycloalkylalkyl), N(cycloalkylalkyl)(aryl), N(cycloalkylalkyl)(arylalkyl), N(cycloalkylalkyl)(heteroaryl), N(cycloalkylalkyl)(heteroarylalkyl), N(aryl)(cycloalkylalkyl), N(aryl)(aryl), N(aryl)(arylalkyl), N(aryl)(heteroaryl), N(aryl)(heteroarylalkyl), N(arylalkyl)(arylalkyl),N(arylalkyl)(heteroaryl), N(arylalkyl)(heteroarylalkyl), N(heteroaryl)(heteroaryl), N(heteroaryl)(heteroarylalkyl), N(heteroarylalkyl)(heteroarylalkyl).
The tem xe2x80x9cacidxe2x80x9d refers to C(xe2x95x90O)OH.
The term xe2x80x9cketonexe2x80x9d refers to C(xe2x95x90O)alkyl, C(xe2x95x90O)cycloalkyl, C(xe2x95x90O)cycloalkylalkyl, C(xe2x95x90O)aryl, C(xe2x95x90O)arylalkyl, C(xe2x95x90O)heteroaryl, C(xe2x95x90O)heteroarylalkyl.
The term xe2x80x9cesterxe2x80x9d refers to a group such as C(xe2x95x90O)Oalkyl, C(xe2x95x90O)Ocycloalkyl, C(xe2x95x90O)Ocycloalkylalkyl, C(xe2x95x90O)Oaryl, C(xe2x95x90O)Oarylalkyl, C(xe2x95x90O)Oheteroaryl, C(xe2x95x90O)Oheteroarylalkyl.
The term xe2x80x9camidexe2x80x9d refers to a group such as, C(xe2x95x90O)NH2, C(xe2x95x90O)NHalkyl, C(xe2x95x90O)NH(cycloalkyl), C(xe2x95x90O)NH(cycloalkylalkyl), C(xe2x95x90O)NH(aryl), C(xe2x95x90O)NH(arylalkyl), C(xe2x95x90O)NH(heteroaryl), C(xe2x95x90O)NH(heteroarylalkyl), C(xe2x95x90O)N(alkyl)(alkyl), C(xe2x95x90O)N(alkyl)(cycloalkyl), C(xe2x95x90O)N(alkyl)(cycloalkylalkyl), C(xe2x95x90O)N(alkyl)(aryl), C(xe2x95x90O)N(alkyl)(arylalkyl), C(xe2x95x90O)N(alkyl)(heteroaryl), C(xe2x95x90O)N(alkyl)(heteroarylalkyl), C(xe2x95x90O)N(cycloalkyl)(cycloalkyl), C(xe2x95x90O)N(cycloalkyl)(cycloalkylalkyl), C(xe2x95x90O)N(cycloalkyl)(aryl), C(xe2x95x90O)N(cycloalkyl)(arylalkyl), C(xe2x95x90O)N(cycloalkyl)(heteroaryl), C(xe2x95x90O)N(cycloalkyl)(heteroarylalkyl), C(xe2x95x90O)N(cycloalkylalkyl)(cycloalkylalkyl), C(xe2x95x90O)N(cycloalkylalkyl)(aryl), C(xe2x95x90O)N(cycloalkylalkyl)(arylalkyl), C(xe2x95x90O)N(cycloalkylalkyl)(heteroaryl), C(xe2x95x90O)N(cycloalkylalkyl)(heteroarylalkyl), C(xe2x95x90O)N(aryl)(cycloalkylalkyl), C(xe2x95x90O)N(aryl)(aryl), C(xe2x95x90O)N(aryl)(arylalkyl), C(xe2x95x90O)N(aryl)(heteroaryl), C(xe2x95x90O)N(aryl)(heteroarylalkyl), C(xe2x95x90O)N(arylalkyl)(arylalkyl), C(xe2x95x90O)N(arylalkyl)(heteroaryl), C(xe2x95x90O)N(arylalkyl)(heteroarylalkyl), C(xe2x95x90O)N(heteroaryl)(heteroaryl), C(xe2x95x90O)N(heteroaryl)(heteroarylalkyl), C(xe2x95x90O)N(heteroarylalkyl)(heteroarylalkyl).
The term xe2x80x9cureaxe2x80x9d refers to a group such as NHC(xe2x95x90O)N(alkyl)(alkyl), NHC(xe2x95x90O)N(alkyl)(cycloalkyl), NHC(xe2x95x90O)N(alkyl)(cycloalkylalkyl), NHC(xe2x95x90O)N(alkyl)(aryl), NHC(xe2x95x90O)N(alkyl)(arylalkyl), NHC(xe2x95x90O)N(alkyl)(heteroaryl), NHC(xe2x95x90O)N(alkyl)(heteroarylalkyl), NHC(xe2x95x90O)N(cycloalkyl)(cycloalkyl), NHC(xe2x95x90O)N(cycloalkyl)(cycloalkylalkyl), NHC(xe2x95x90O)N(cycloalkyl)(aryl), NHC(xe2x95x90O)N(cycloalkyl)(arylalkyl), NHC(xe2x95x90O)N(cycloalkyl)(heteroaryl), NHC(xe2x95x90O)N(cycloalkyl)(heteroarylalkyl), NHC(xe2x95x90O)N(cycloalkylalkyl)(cycloalkylalkyl), NHC(xe2x95x90O)N(cycloalkylalkyl)(aryl), NHC(xe2x95x90O)N(cycloalkylalkyl)(arylalkyl), NHC(xe2x95x90O)N(cycloalkylalkyl)(heteroaryl), NHC(xe2x95x90O)N(cycloalkylalkyl)(heteroarylalkyl), NHC(xe2x95x90O)N(aryl)(cycloalkylalkyl), NHC(xe2x95x90O)N(aryl)(aryl), NHC(xe2x95x90O)N(aryl)(arylalkyl), NHC(xe2x95x90O)N(aryl)(heteroaryl), NHC(xe2x95x90O)N (aryl)(heteroarylalkyl), NHC(xe2x95x90O)N(arylalkyl)(arylalkyl), NHC(xe2x95x90O)N(arylalkyl)(heteroaryl), NHC(xe2x95x90O)N(arylalkyl)(heteroarylalkyl), NHC(xe2x95x90O)N(heteroaryl)(heteroaryl), NHC(xe2x95x90O)N(heteroaryl)(heteroarylalkyl), NHC(xe2x95x90O)N(heteroarylalkyl)(heteroarylalkyl).
The term xe2x80x9chalogenxe2x80x9d refers to chlorine, fluorine, bromine, and iodine.
The wedge or hash is only one representation of a stereochemical descriptor. All stereoisomers, including enantiomers and diastereomers, are included within Formulas 1-8 and are provided by this invention. When specific isomers are drawn, they are the preferred isomers.
In some situations, compounds may exist as tautomers. All tautomers are included within Formulas 1-8 and are provided by this invention.
When compounds are administered, some metabolism may occur. All metabolites are included within Formulas 1-8 and are provided by this invention.
When a bond to a substituent is shown to cross the bond connecting 2 atoms in a ring, then such substituent may be bonded to any atom in the ring, provided the atom will accept the substituent without violating its valency. When there appears to be several atoms of the substituent that may bond to the ring atom, then it is the first atom of the listed substituent that is attached to the ring.
When a bond is represented by a line such as xe2x80x9c---,xe2x80x9d this is meant to represent that the bond may be absent or present provided that the resultant compound is stable and of satisfactory valency.
Compounds of the present invention are capable of forming acid addition salts (see for example, Berge S. M., et al., xe2x80x9cPharmaceutical Salts,xe2x80x9d Journal of Pharmaceutical Science, 1977:1-10) with inorganic acids such as, for example, hydrochloric acid, sulfuric acid and the like, as well as salts derived from organic acids such as, for example, aliphatic mono and dicarboxylic acids or aliphatic and aromatic sulphonic acids. The acid addition salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt. The free base form may be regenerated by contacting the salt form with a base. While the free base more may differ from the salt form in terms of physical properties, such as solubility, the salts are equivalent to their respective free bases for the purposes of the present invention.
Certain compounds of the present invention can exist in unsolvated form as well as solvated form including hydrated form. In general, the solvated form including hydrated form is equivalent to unsolvated form and is intended to be encompassed within the scope of the present invention.
xe2x80x9cProdrugsxe2x80x9d are intended to include any covalently bonded carrier which releases the active parent drug according to Formulas 1-8 in vivo. Examples of prodrugs include acetates, formates, benzoate derivatives of alcohols and amines present in compounds of Formulas 1-8. They also include derivatives of the amidine or guanine functionality and would include C(xe2x95x90NR3)NH2 where R3 is selected from OH, NH2, C1-4 alkoxy, C6-10 aryloxy, C1-10 alkoxycarbonyl, C6-10 aryloxycarbonyl. Preferred derivatives include examples wherein R3 is OH, NH2, methoxy, and ethoxycarbonyl.
The following table provides a list of abbreviations and definitions thereof used in the present invention.
Also provided by this invention is a method for preventing and treating acute, subacute, and chronic thrombotic disorder in a mammal comprising administering to such mammal an effective amount of a compound of Formulas 1-8. The compounds are useful as anticoagulants for the treatment and prophylaxis of disorders such as venous and arterial thrombosis, pulmonary embolism. and ischemic events such as myocardial infarction or cerebral infarction. These compounds also have therapeutic utility for the prevention and treatment of complications of indwelling vascular access ports and arteriovenous shunts and coagulopathies associated with cardiopulmonary bypass or other extracorporeal systems. These compounds are useful for preventing or treating unstable angina, refractory angina, intermittent claudication, disseminated intravascular coagulation, and ocular buildup of fibrin. Since thrombin and serine proteases have also been demonstrated to activate a number of different cell types, these compounds are useful for the treatment or prophylaxis of septic shock and other inflammatory responses such as acute or chronic atherosclerosis. The compounds also have utility in treating neoplasia/metastasis and neurodegenerative diseases such as Alzheimer""s and Parkinson""s disease. In a preferred method, the thrombotic disorder is selected from venous thrombosis, arterial thrombosis, pulmonary embolism, myocardial infarction, cerebral infarction, angina, cancer, diabetes. A further embodiment of this invention is a pharmaceutical formulation comprising a compound of Formulas 1-8 administered with a diluent, excipient, or carrier thereof.
The compounds of Formulas 1-8 can be prepared by any of various methods known to those skilled in the art of organic chemistry. The following general schemes represent preferred routes to provide the compounds of this disclosure. The reactions are typically performed in solvents appropriate to the reagents and substrates employed. It is understood that functionality present in the molecule must be compatible with the reagents and reaction conditions proposed. Not all compounds of Formulas 1-8 falling into a given class may be compatible with some of the reaction conditions described. Such restrictions are readily apparent to those skilled in the art of organic synthesis, and alternative methods must then be used. 
Step a:
The aldehyde is converted to the trichloromethyl carbinol by treatment with carbon tetrachloride and aluminum/lead bromide DMF at room temperature according to the procedure of Tanaka J., Org. Chem., 1989:444. Alternative procedures include the addition of trimethylsilyl trichloromethane and tetrabutylammonium fluoride or more typically chloroform and potassium hydroxide as exemplified by Galun, Org. Synth. Coll., 1973; V:130. It should also be noted that trimethylsilyl trichloroacetate in the presence of potassium fluoride is an effective process for the preparation of trichlormethylcarbinols as exemplified by Weissman, Org. Proced. Int., 1995;27(5):590-592.
Step b:
Addition of o-aminophenol and base affords the benzoxazinone in a manner similar to the procedure of Gukasyan et al., Arm. Khim. Zh., 1988;41(9):572-575. This typically involves treatment of the trichloromethyl carbinol with a suitably substituted ortho-amino phenol in a solvent such as DMF or DMSO in the presence of potassium hydroxide or sodium hydride at room temperature to 100xc2x0 C. It is apparent that by employing choral trichloromethyl carbinol, the resulting benzoxazinone will be obtained in chiral form.
Step c:
Alkylation is typically achieved by treatment with an appropriate electrophile and by the addition of a base in a dipolar aprotic solvent. Typical conditions include, for example, use of a bis-electrophilic substrate such as 1,5-dibromopentane in a dipolar aprotic solvent such as DMF or DMSO and addition of a base, such as sodium hydride. Alternatively, alkylation can be achieved by the addition of a phase transfer reagent such as an alkylammonium salt, such as benzyltriethylammonium chloride, and employing a base such as sodium ethoxide. Reaction rates are typically improved by the application of heat, and hence, reactions are run at from 0xc2x0 C. to 70xc2x0 C.
Step d:
Treatment with an amine, such as cis-2,6-dimethylpiperidine at an elevated temperature such as 50xc2x0 C. affords the expected N-alkylated piperidine. The amine may be used as solvent, or alternatively, the amine may be added in stoichiometric proportions and the reaction mixture refluxed in a solvent such as ethanol, acetonitrile, or toluene. The product, as the appropriate acid addition salt, is then neutralized by the addition of base such as aqueous potassium hydroxide. In situations where the amine is volatile, then the reaction mixture is heated, typically from 50xc2x0 C. to 150xc2x0 C., in a sealed tube.
Step e:
Conversion of the nitrile to the hydroxyamidine is achieved by allowing the nitrile to react with hydroxylamine in methanol at room temperature. Typically, hydroxylamine hydrochloride is added to the nitrile containing substrate at room temperature, and the reaction is initiated by the addition of base such as potassium carbonate or diisopropylethylamine. The reaction is usually monitored by HPLC to determine the absence of starting material, the nitrile, and are typically complete within a 24-hour period.
Step f:
The amidoxime is activated by the addition of acetic anhydride of trifluoroacetic anhydride intermediate in a solvent such as acetic acid or trifluoroacetic acid to afford the O-acylated intermediate, which may be isolated or alternatively used directly in the subsequent reduction step. This step and the subsequent reduction may be combined, i.e., the reduction with Pd/C is performed in acetic anhydride/acetic acid, or trifluoroacetic anhydride/trifluoroacetic acid.
Step g:
The substrate is dissolved in methanol, or acetic acid, or trifluoroacetic acid, and treated with a transition metal catalyst such as Palladium dispersed on carbon and is then hydrogenated briefly, typically for 1 to 12 hours. The product is then isolated, typically by crystallization or via chromatography such as reverse phase HPLC.
Alternative procedures for the synthesis of the parent benzoxazinone include. for example in scheme 2: 
Step a:
Treatment of the methyl alpha-bromo phenylacetate with ortho-nitrophenol and base readily affords the phenolic ether. Of course, it is realized that activation of the benzylic carbon as a chloride or mesylate would also suffice to allow the initial etherification to proceed. Typically, the potassium or sodium salt of ortho-nitrophenol is added to the electrophile in a solvent, such as DMF, and the mixture warmed, typically to 50xc2x0 C., until the reaction is judged complete by TLC. Use of a chiral alpha-functionalized aryl acetate would afford the chiral adduct.
Step b:
Reduction of the nitro group to the corresponding aniline is readily achieved with a transition metal such as palladium on carbon or Raney nickel and hydrogen or alternatively by treatment with tin in aqueous hydrochloric acid. These anilines readily cyclize to the corresponding benzoxazinone during the reduction or upon warning in a solvent such as methanol.
Step c:
Alternatively upon addition of ortho-aminophenol according to the procedure of Bull. Soc. Chim. Belg., 1987:473-480, the benzoxazine-2-one is isolated directly.
A further alternative procedure for the preparation of the requisite benzoxazinones requires the treatment of the substituted amino phenol with the acid chloride as shown in Scheme 3 in a manner similar to that described by Krapcho, Tawada et al., Chem. Pharm. Bull., 1990:1238-1245. 
Step a:
The ortho amino phenol is treated with the acid chloride in a solvent such as dichloromethane in the presence of a base such as diisopropylethylamine to afford the N-acylated product.
Step b:
Treatment with a base such as potassium carbonate in a solvent such as DMF then affords the parent benzoxazinone via an intramolecular nucleophilic addition of the phenoxide to the secondary bromide.
A further alternative procedure is outlined in Scheme 4 which is initiated by etherification of an ortho-halo phenol with an alpha-bromo phenylacetamide. Subsequent intramolecular nucleophilic substitution then affords the N-alkylated benzoxazinone (Coutts and Southcott J., Chem. Soc., Perkin Trans. I, 1990:767-771). 
Step a:
The sodium salt of the phenol is treated with the electrophile in a solvent such as methylene chloride or dioxane, and then the reaction mixture is warmed to 100xc2x0 C. for 4 hours.
Step b:
Addition of sodium hydride in a solvent such as DMPU and warming to 100xc2x0 C. affords the required benzoxazinone.
Scheme 5 demonstrates another alternative procedure that may be employed. 
Step a:
2-Hydroxy-2H-1,4-benzoxazin-3(4H)-one is prepared by the procedures of Sahu A. Indian Journal of Chemistry, 1990;603-605, or Matlin S A, JCS Perkin Trans I, 1979;2481-2487 and is then treated with HBr in acetic acid/acetic anhydride to afford 2-bromo-2H-1,4-benzoxazin-3(4H)-one at room temperature for 24 to 48 hours, according to the procedure of Tietze LF, Synthesis, 1991;1118-1120. The product precipitates from the reaction mixture and due to its hydrolytic instability is used directly in the subsequent reaction step. Alternatively the acetate may be prepared by treating the alcohol with acetic anhydride in the presence of pyridine and catalytic DMAP. Addition of HBr in acetic acid to this acetate again affords the corresponding bromide.
Step b:
Addition of a phenol or phenolic ether, such as 4-bromo anisole and a Lewis acid, such as tin (IV) chloride or aluminum (III) chloride. affords after refluxing for several hours the corresponding 2-aryl substituted benzoxazinone.
Steps c-f:
Performed in a manner similar to the previous schemes
The substituted alpha-bromo phenylacetates used in these reactions are prepared by a number of standard procedures such as those shown in Scheme 6. 
Acetic acid derivatives are prepared by conversion of the substituted benzoic acid to the corresponding acid chloride with. for example, oxalyl chloride and catalytic DMF and is then treated with ethereal diazomethane. Rearrangement with silver oxide in an alcoholic solvent, such as methanol, affords the homologated acetic acid methyl ester. Functionalisation of the alpha position is then achieved by refluxing a solution of the ester in carbon tetrachloride with N-bromosuccinimide in the presence of a radical initiator such as AIBN. It is also readily apparent that treatment of acetic acid derivatives with bromine in the presence of phosphorus tribromide will afford the alpha-bromo phenyl acetate in a manner similar to the named reaction Hell-Volhard-Zelinskii.
Alternatively, the intermediate alpha bromo ester may be prepared by the procedure shown in Scheme 7 according to the procedure of Robert A., Jaguelin S., Guinamant J. L. xe2x80x9cSynthesis of esters of xcex1-halo acids from gem dicyano epoxides. Tetrahedron, 1986;42(8):2275-2281. 
In this situation the aldehyde, such as 3-bromobenzaldehyde as a representative example, is reacted with malononitrile in the presence of catalytic piperidine in a solvent such as dioxane to afford the 2-[(3-bromophenyl)methylene]malononitrile. Epoxide formation proceeds readily with commercial bleach at a pH of 5 to 6. Treatment with hydrobromic acid in methanol then affords the required methyl 2-bromo-2-(3-bromophenyl)acetate. Similarly prepared was methyl 2-bromo-2-(3-cyanophenyl)acetate
Alternative procedures for the conversion of nitriles to amidines are also available as shown in Scheme 8. The nitrile in turn are available by, for example, a palladium catalyzed cross-coupling reaction with Zn(CN)2 or via treatment of the aryl bromide at elevated temperatures with copper (I) cyanide. Treatment of the nitrile with hydrogen chloride in an alcoholic solvent affords the corresponding iminoether hydrochloride. These intermediates are then treated with source of ammonia, for example ammonia in methanol, or ammonium chloride, or ammonium acetate, and the mixture is stirred, and warmed if necessary, to afford the amidine. 
The benzothiazinone of Formula 1 may also be prepared according to Scheme 9. 
The reaction sequence is similar to that described in Scheme 1 except that 2-aminophenyl thiol replaces 2-aminophenol in the initial reaction sequence.
Since some of the compounds of Formula 1 exist as a mixture of enantiomers. it is often desirable to prepare the optically pure material. In these situations, the addition salts with chiral acids are prepared and the mixture separated by crystallization. The parent compounds may then be liberated by treatment with base, such as potassium hydroxide. Enantiomers may also be separated by chiral HPLC. Suitable columns for separating enantiomers of intermediates such as 3-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)benzenecarbonitrile include beta-cyclodextrin (keystone chiral xcex2-PM) employing 50% water and acetonitrile mixtures. Alternatively, an asymmetric synthesis may be employed for the synthesis of a specific enantiomer. In particular, a suitably substituted phenoxide (for benzoxazinones) or thiophenoxide (for benzothiazinones) may be added to a pentolactone derivative, as described by Koh, J. Org. Chem., 1994;59:4683-4686 and outlined in Scheme 10. 
Use of (R) pantolactone esters affords the (S) diastereomer. In this scheme, Y is a substituent that may be elaborated to afford an aniline which undergoes intramolecular cyclization to afford the required chiral benzoxazinone. Examples of such substituents would include a nitro functionality or N-acetyl group.
A further alternative procedure for the generation of chiral benzoxazinone intermediates is available by application of lactamide derived esters of racemic alpha-halo carboxylic acids (Devine, Tetrahedron Letts., 1996:2683-2686) as outlined in Scheme 11. 
The diastereoselectivity of this reaction is good, and the products are of the (R) stereochemistry providing a complementary approach to that of Scheme 10.
It should be noted that chiral alpha-trichloromethyl carbinols afford optically active alpha-aryloxy acids upon treatment with phenoxide providing yet another alternative method to preparing chiral benzoxazinones or benzothiazinones (Corey, Tetrahedron Lett., 1992:3431).
Another procedure for preparing chiral benzoxazinones is outlined in Scheme 12 
Step a:
The aldehyde is protected via the formation of a suitable protecting group, which in the above scenario is a benzylether, with for example potassium carbonate or sodium hydroxide and benzyl bromide in a solvent such as DMF or ethanol.
Step b:
Addition of cyanide to the aldehyde readily forms the intermediate cyano hydrin in a solvent such as methanol. It is envisioned that this process may also be performed in an assymetric manner by use of any one of the following general procedures Danda, H et al., Chem Lett 1991, 731. Poly(quinidine-co-acrylonitrile) Effenberger, F et al., Tetrahedron Lett 1990, 31 (9), 1249. (Oxynitrilase) Mori, A. et al., Chem Lett 1989(12), 2119. Cyclo-(Leu-His) or Tanaka, K. et al., J Org Chem 1990, 55, 181. cyclo((S)-Phe-(S)-His) Minamikawa, H. et al., Bull Chem Soc Jpn 1988, 61 (12), 4379. 1,1,4,4-Tetraphenylbutanetetraol-(2R,3R)-O,O-phenylethylidene Ti(i-PrO)2Cl2 Harrington, K. J et al., Aust J Chem 1986, 39, 1135.1) beta-Cyclodextrin
Steps c:
Conversion of the cyano functional group to a methyl ester is readily achieved by treatment of the nitrile with HCl gas in an alcoholic solvent such as methanol. Addition of water then readily converts the intermediate imino ether to the ester.
Step d:
Oxidation of the alcohol to the keto-ester is readily achieved with an oxidising agent such as oxalyl chloride and dimethylsulfoxide or by heating with manganese dioxide in a solvent such as toluene or methylene chloride.
Step e:
Chiral reduction of the keto-ester is best achieved with a reducing agent like R-alpine borane. This reduction is typically slow and takes several days to complete.
Step f:
A Mitsunobo coupling reaction is then performed on this chiral alcohol employing nitro phenol (or possibly amino phenol), diisopropylazodicarboxalate (or other alkylazodicarboxylate) and triphenylphosphine in a solvent such as ethylacetate at a low temperature such as xe2x88x9240xc2x0 C.
Step g:
Reduction of the nitro group is best achieved with neutral Raney Nickel and a hydrogen atmosphere in a solvent such as methanol. It is important that the solution does not become basic since a reduction in enantiomeric excess may be observed.
Compounds of the present invention are further characterized by their ability to inhibit the catalytic activity of factor Xa, which is demonstrated in the assay as follows. Compounds of the present invention may be prepared for assay by dissolving them in buffer to give solutions ranging in concentrations from 1 to 100 xcexcM. In an assay to determine the inhibitory dissociation constant, Ki, for a given compound, a chromogenic or fluorogenic substrate of factor Xa would be added to a solution containing a test compound and factor Xa; the resulting catalytic activity of the enzyme is spectrophotometrically determined. This assay is well-known to those skilled in the art and is commonly used to determine antithrombotic activity.
The compounds of the present invention may be used as anti-coagulants in vitro or ex vivo as in the case of contact activation with foreign thrombogenic surfaces such as is found in tubing used in extracorporeal shunts. The compounds of the invention may also be used to coat the surface of such thrombogenic conduits. To this end, the compounds of the invention can be prepared as lyophilized powders, redissolved in isotonic saline or similar diluent, and added in an amount sufficient to maintain blood in an anticoagulated state.
The therapeutic agents of the present invention may be administered alone or in combination with pharmaceutically acceptable carriers. The proportion of each carrier is determined by the solubility and chemical nature of the compound, the route of administration, and standard pharmaceutical practice. For example, the compounds may be injected parenterally; this being intramuscularly, intravenously, or subcutaneously. For parenteral administration, the compound may be used in the form of sterile solutions containing other solutes, for example, sufficient saline or glucose to make the solution isotonic. The compounds may be administered orally in the form of tablets, capsules, or granules containing suitable excipients such as starch, lactose, white sugar and the like. The compounds may also be administered sublingually in the form of troches or lozenges in which each active ingredient is mixed with sugar or corn syrups, flavoring agents, and dyes, and then dehydrated sufficiently to make the mixture suitable for pressing into solid form. The compounds may be administered orally in the form of solutions which may contain coloring and/or flavoring agents. Typical formulations will contain from about 5% to 95% by weight of an invention compound.
The amount of invention compound to be utilized to prevent and treat thrombotic disorders is that amount which is effective to prevent or treat the condition without causing unacceptable side effects. Such effective amounts will be from about 0.01 mg/Kg to about 500 mg/Kg, preferably from about 1 mg/Kg to about 100 mg/Kg. Physicians will determine the precise dosage of the present therapeutic agents which will be most suitable. Dosages may vary with the mode of administration and the particular compound chosen. In addition, the dosage may vary with the particular patient under treatment.
When the composition is administered orally, a larger quantity of the active agent will typically be required to produce the same effect as caused with a smaller quantity given parenterally.